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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`HOLOGIC, INC.,
`and BECTON, DICKINSON AND COMPANY,
`Petitioners
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`v.
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`ENZO LIFE SCIENCES, INC.
`Patent Owner
`
`____________
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`Case No. IPR2016-00820
`U.S. Patent No. 7,064,197
`____________
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`CORRECTED PETITIONERS’ REPLY
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`Table of Contents
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`PRELIMINARY STATEMENT ..................................................................... 1
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`I.
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`II. ARGUMENTS ................................................................................................ 1
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`A.
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`Claims anticipated by Fish. ................................................................... 1
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`1.
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`2.
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`Single-stranded (ss) nucleic acids fixed to a non-porous
`solid support. ............................................................................... 1
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`Fish’s immobilized ssDNA is in hybridizable form. .................. 4
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`B.
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`Claims obvious based on Fish. .............................................................. 9
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`1.
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`2.
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`Obviousness concerning sequence of interest. ........................... 9
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`Obvious to use Fish’s binding technique for RNA. .................. 10
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`C.
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`Claims obvious based on Fish in view of Gilham. ............................. 10
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`D. Anticipation of challenged claims by VPK. ........................................ 12
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`1.
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`Enzo cannot claim priority to the 1983 application
`because it fails to comply with the written description
`requirement. .............................................................................. 12
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`2.
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`No reduction to practice before VPK’s publication date. ......... 14
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`E.
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`It would have been obvious that the hybridization procedure of
`VPK could be performed on glass slides having wells or
`depressions as disclosed by Metzgar. .................................................. 23
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`F.
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`Obviousness based on Noyes, VPK, and Ramachandran. .................. 24
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`1.
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`Nucleic acids bound using the Noyes binding chemistry
`would remain in hybridizable form. ......................................... 24
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`2. Motivation to combine Noyes and Ramachandran to
`covalently bind RNA in hybridizable form to the glass
`slides of VPK. ........................................................................... 25
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`III. THE SECONDARY CONSIDERATIONS, IF ANY, FAIL TO
`OVERCOME THE EVIDENCE OF OBVIOUSNESS ................................ 25
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`i
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`A.
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`B.
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`Enzo’s technical expert is not qualified to opine on secondary
`considerations. ..................................................................................... 26
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`Enzo has not established a nexus between the merits of the
`claimed invention and any secondary considerations. ........................ 27
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`IV. CONCLUSION .............................................................................................. 28
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`ii
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`I.
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`PRELIMINARY STATEMENT
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`Case No. IPR2016-00820
`U.S. Patent No. 7,064,197
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`The Institution Decision held that it is more likely than not that the
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`challenged claims are unpatentable based on the grounds presented in Hologic’s
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`Petition. Nothing in Enzo’s Patent Owner Response calls that into question. The
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`conclusory and unsupported arguments of Enzo’s technical expert, Dr. Gregory
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`Buck (“Buck”), fail to alter the Board’s reasoning in its Institution Decision. The
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`Board should issue a Final Written Decision canceling the challenged claims.
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`II. ARGUMENTS
`A. Claims anticipated by Fish.
`1.
`Single-stranded (ss) nucleic acids fixed to a non-porous solid
`support.
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`The Decision properly concludes that Fish explicitly discloses binding
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`ssDNA to PLL-coated wells. Decision, 12-13.
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`The Decision states that Fish “knew that ssDNA would bind to PLL-coated
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`wells, because they were relying on such binding to carry out their experiment.”
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`Decision, 13. The Decision quotes the following supporting sentence from Fish:
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`“[t]his positive control for the nuclease S1 activity suggests that single-stranded
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`nucleic acid, bound to PLL treated plastic, remains susceptible to the hydrolytic
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`activity of the enzyme.” Ex.1006, 538, right col.,¶1.
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`Enzo’s alternative interpretation of the sentence—Fish assumed that ssDNA
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`may have bound—does not make sense. Response, 5. The Decision got it right.
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`Enzo claims that “additional information” suggests Fish would not have
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`known ssDNA bound. Response, 5. Enzo argues that prior hybridization methods
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`involved ssDNA bound to porous materials or cells bound to non-porous materials.
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`As a consequence, Enzo argues that a POSITA would not have expected ssDNA to
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`bind to PLL-coated polyvinyl plates. Id. Enzo’s alleged state of the art, which did
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`not address nucleic acids binding to PLL, sheds no light on what the Fish authors
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`knew about binding ssDNA to PLL-coated wells.
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`Enzo oddly asserts that Fish’s doubt that DNA would bind to uncoated
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`polyvinyl somehow counters the Decision’s conclusion that Fish knew ssDNA
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`would bind to PLL-coated polyvinyl. Response, 5.
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`Fish proves that dsDNA bound to the PLL-coated wells. Response, 4;
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`Ex.1035, 56:25-57:5. Enzo argues that those dsDNA experiments were unreliable
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`for assessing whether ssDNA would bind in view of unspecified differences
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`between ssDNA and dsDNA. Ex.2042, ¶76. But both ssDNA and dsDNA have
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`negatively-charged backbones, allowing them to bind to positively-charged PLL-
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`coated wells. Ex.1002, ¶52. Thus, if dsDNA binds to PLL-coated plates, there is no
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`reason to doubt that ssDNA would too. Id.
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`Enzo argues that the antibodies in Fish could only detect dsDNA, not
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`ssDNA, because Fish’s assay was designed to detect antibodies that bound to
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`dsDNA, not ssDNA. Response, 5-6, 8. Indeed, Fish’s goal was designing an assay
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`for detecting antibodies that bind to dsDNA. However, to achieve that goal, the
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`experiments depicted in Figs. 1, 3-4 used antibodies that bind to ssDNA. (See
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`Nelson’s testimony concerning detection of antibodies that bind to ssDNA:
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`Ex.2017, 114:14-23; 124:18-125:4; 125:10-18.) Fig. 1 used ssDNA antibody
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`binding as a positive control to assess the purity of the dsDNA to be used in the
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`anti-dsDNA assay. Ex.2042, ¶79. Ex.1006, 538, right col., ¶1. Figs. 3-4 assessed
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`“[a]nti-ssDNA activity in patient and normal sera.” Ex.1002, ¶49; Ex.1006, 540-
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`541, Fig. 3-4 figure legends. That assessment showed that anti-ssDNA antibodies
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`bound to ssDNA in normal sera with too much frequency—informing Fish that
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`“[b]inding to this type of single-stranded nucleic acid therefore appears to have no
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`diagnostic value.” Ex.1006, 539, first full ¶, left col.
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`Rather than accept the peer-reviewed data as disclosing exactly what it
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`shows, Enzo creates an unsupported, alternate theory. Enzo tries to attribute the
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`results in Figs. 1, 3-4 to non-specific, background binding of antibodies to wells
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`having no bound ssDNA. Ex.2042, ¶¶85, 90-91. But Fish optimized conditions to
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`alleviate such background by adding a solution of BGG and BSA to the wells to
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`block non-specific binding. Ex.1002, ¶¶49-50; Ex.1035, 119:1-7; 122:20-123:5.
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`Fish also included negative control wells not treated with DNA (DNA-) to subtract
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`out background signal from the results obtained with DNA treated wells (DNA+).
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`Ex.2042, ¶84; Ex.1035, 127:22-128:2. Thus, the positive signals attributed to
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`antibodies binding to immobilized ssDNA in Figs. 1, 3-4 already had background
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`signal subtracted out. Id.
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`Nelson never agreed that the results in the figures were due to background,
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`and testified that the optimized conditions suggest otherwise. Ex.2017, 88:2-16;
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`89:6-17, 120:13-18. Also, Nelson’s agreement that background signal occurred in
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`some of the DNA- wells (Response, 7) does not indicate Fish’s experiments were
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`flawed, because the background signal from the DNA- wells was subtracted from
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`the signals in the DNA+ wells (discussed above).
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`Finally, Fig. 1 confirms that ssDNA was bound because S1 nuclease did not
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`digest the dsDNA. Decision, 10, citing Ex.1006, 538, right col.¶1.
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`Fish’s immobilized ssDNA is in hybridizable form.
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`2.
`Petitioner adequately shows that ssDNA bound to the PLL-coated wells in
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`Fish necessarily was “in hybridizable form.” Hologic explained why Fish’s bound
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`ssDNA was in hybridizable form. Petition, 25-29. The Decision agreed. Contrary
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`to Enzo’s argument, the claim term “in hybridizable form” was not ignored.
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`Enzo also argues that nucleic acids may be bound to a support in way that
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`renders it non-hybridizable. Response, 11. But the articles Buck cites discuss
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`slowing down—not preventing—the rate of hybridization. Ex.2042, ¶95, citing
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`Exs.2012, 2013; Ex.1035, 130:15-133:10. Buck’s declaration at ¶95 provides no
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`facts that suggest why ssDNA bound to the PLL-coated well in Fish is prevented
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`from hybridizing.
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`In fact, Buck presents evidence showing that ssDNA will be in hybridizable
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`form when bound to amines on the surface of a support, because the binding
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`interaction involves the phosphate backbone of the ssDNA, and not the bases.
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`Ex.2042, ¶225. Buck testifies that such binding of ssDNA leaves the bases
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`“potentially available to bind with the corresponding Watson-Crick bases of
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`second nucleic acid in a hybridization reaction as can be seen in the image below:
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`”
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`Id. Buck’s diagram shows positively-charged amines (NH3
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`+) on the surface
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`interacting with the negatively-charged ssDNA phosphate backbone, leaving the
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`bases on the top of the DNA strand available for hybridization.
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`Although Buck’s discussion in ¶225 involves a different way of presenting
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`amines on the surface than PLL coating, PLL also presents amines on the surface.
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`Thus, binding of ssDNA to PLL also involves interaction between positively-
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`charged amines and the negatively-charged phosphate backbone of ssDNA.
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`Ex.1035, 63:6-64:17; Ex.1002, ¶¶43, 52. Thus, the binding of ssDNA to the PLL-
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`coated plates in Fish would also leave the bases available to bind with
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`complementary bases. Nothing presented by Enzo counters Buck’s own evidence.
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`The ’197 patent includes a single sentence suggesting the use of PLL coating
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`to bind ssDNA. Ex.1001, 11:37-39. The patent includes no disclosure of any PLL
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`concentrations or any other factors or conditions that must be used to bind ssDNA
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`in hybridizable form, and presents no actual hybridization experiments using PLL-
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`coated supports. Yet Enzo now argues that even if ssDNA is bound to PLL,
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`multiple factors are critical for the bound ssDNA to be capable of hybridizing.
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`Enzo presents no facts suggesting how those factors could prevent ssDNA, bound
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`to the PLL-coated surface in Fish, from hybridizing under appropriate conditions.
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`Nelson explained why Diehl (Ex. 1021) provides additional confirmation
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`that ssDNA, bound to a PLL-coated wells in Fish, would be in hybridizable form.
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`Ex.1002, ¶¶55-61. Enzo points to differences between Diehl’s and Fish’s PLL
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`coating protocol and solid supports, but provides no reasoning why any of those
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`differences would bring into doubt the hybridization capability of the ssDNA
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`bound to the Fish wells.1
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`Many of Enzo’s arguments focus on possible differences in binding of
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`ssDNA to a solid support, but Fish showed that ssDNA bound to the PLL-coated
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`wells. Enzo also argues that several factors could impact hybridization capability,
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`but offers no facts to support those positions. Ex.2042, ¶¶107, 114.
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`1 See Ex. 1037 addressing Enzo’s concern about Ex.1032.
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`Enzo argues Fish discloses no hybridization conditions, although the
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`challenged claims lack such a requirement, which the Decision noted. Response,
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`14-15, 19-20.
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`Nelson did not admit that certain factors will alter the ability of the bound
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`ssDNA to hybridize in the five transcript citations at the Response, 15—he stated
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`they could change hybridization conditions. For example, just prior to the
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`discussion at 151:25-152:7 cited by Enzo, Nelson testified that nucleic acid length
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`could change the conditions used for hybridization, “but no, it doesn’t alter the
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`ability to hybridize.” Ex.2017, 151:5-14.
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`Enzo argued that PLL binding was not involved in Diehl’s UV cross-linking
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`attachment method. Response, 19. But Buck agreed that ssDNA in Diehl was
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`bound by both UV cross-linking and PLL. Ex.1035, 136:9-137:1. Nelson
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`explained why the UV cross-linking would be more likely to prevent hybridization
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`than PLL binding. Ex.1002, ¶61. Enzo offers no facts or reasoning to counter that
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`testimony. Enzo also fails to explain why betaine would impact bound ssDNA’s
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`ability to hybridize.
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`B. Claims obvious based on Fish.
`1. Obviousness concerning sequence of interest.
`Lack of a specific disclosure of a claimed invention does not indicate that
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`the claim is non-obviousness and fails to prove skepticism or no expectation of
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`success.
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`Enzo offers Buck’s unsupported conclusions that there was skepticism in the
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`art that non-porous solid supports could be used for ssDNA hybridization.
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`Reponse, 25. Buck fails to explain what “art” he is basing his conclusions on.
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`When asked about specific interactions of ssDNA attachment to porous solid
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`supports in his experience, Buck responded several times that he really just cared
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`that it worked, he did not care why. Ex.1035, 22:4-15, 23:18-24:2. When asked
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`about a nucleic acid binding technique, Buck could not answer, stating “I’m not a
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`chemist.” Id., 169:9-20. Without providing facts showing why a POSITA would
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`have the concerns listed in Buck’s declaration at ¶128, the Board should give no
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`weight to his conclusions.
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`In contrast and as noted above, the record shows that the negatively-charged
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`backbone of ssDNA was known to interact with PLL-coated material. Ex. 1035,
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`63:6-64:17; Ex.1002, ¶¶43, 52. Enzo offers no facts why such binding, which
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`leaves the bases available for hybridization, would have been inappropriate for
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`hybridization.
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`Finally, Enzo attempts to change the term “nucleic acid sequence of interest”
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`to exclude known sequences that hybridize to a target. Response, 26. The Decision,
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`correctly concludes that “[i]f a nucleic sequence is of interest so too is its
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`complementary sequence, because the nucleotides of the sequence have known
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`base pairings . . . .” Decision, 22. Enzo proves no facts to suggest otherwise.
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`2. Obvious to use Fish’s binding technique for RNA.
`Enzo argues that Fish teaches away from using RNA because the antibodies
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`in Fish are directed to DNA. Response, 26-28. But Nelson’s testimony involved
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`using the immobilization techniques of Fish to attach RNA, not using RNA in
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`Fish’s antibody detection method. Ex.1002, ¶79.
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`C. Claims obvious based on Fish in view of Gilham.
`Rather than address the explanation of the chemistry involved in Gilham’s
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`ssDNA attachment technique presented by Nelson, Enzo offers inaccurate
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`testimony of a witness who had difficulty understanding the involved chemistry.
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`Enzo argues that a POSITA would not have applied the Gilham chemistry to non-
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`porous solid supports, but again, offered no facts supporting that conclusion.
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`Response, 29, Ex.2042, ¶138. A POSITA would have known that PLL-coated
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`wells have amines on the surface, which are available for the Gilham binding
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`chemistry. Ex.1002, ¶¶43, 82.
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`Buck also opined, without support, that the Gilham chemistry “would likely
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`involve unintended side reactions.” Ex.2042, ¶138. When asked if he was aware of
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`any side reactions that could prevent RNA from hybridizing, Buck answered
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`“[w]ell the answer is I’m not a chemist. I wouldn’t be able to say whether there
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`could be one or not.” Ex.1035, 169:9-20.
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`Buck also confused two completely different attachment chemistries as
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`being part of the same technique. Buck thought that Gilham used a carbodiimide
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`activating agent in a completely different binding technique relied upon by Nelson.
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`Ex.2042, ¶137. This misunderstanding is important. Buck relied upon alleged non-
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`specific binding associated with carbodiimide—a technique not cited by Nelson—
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`to question the reliability of Nelson’s testimony about Gilham. Ex.2042, ¶142;
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`Ex.1035, 157:16-158:6. Even if non-specific binding were an issue, Buck testified
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`that treatments to address that issue were well known. Ex.1035, 76:2-78:23.
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`Enzo also questioned whether the RNA bound in Gilham would be capable
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`of hybridization. Response, 30. But, the RNA in Gilham is bound at only the 3’-
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`end, leaving the rest of the nucleotides available for hybridization. Ex.1002, ¶¶81-
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`82. Enzo erroneously argued that Gilham did not involve hybridization and Nelson
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`failed to say that it did. Response, 30; Ex.2042, ¶141. But Gilham clearly discloses
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`hybridization and Nelson testified about it. Ex.1019, 179, first full ¶; Ex.1002,
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`¶¶80-81.
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`Enzo further confused Nelson’s position as suggesting the use of RNA in
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`Fish’s antibody detection technique. Response, 30. But instead, Nelson suggested
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`using the Fish PLL-coated wells to perform the Gilham covalent bonding for RNA
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`hybridization assays. Ex.1002, ¶83; Ex.2017, 192:6-13.
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`D. Anticipation of challenged claims by VPK.
`Enzo attempts to disqualify VPK as prior art by arguing that the claims are
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`entitled to the benefit of a January 1983 filing date, and that the claims are entitled
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`to an even earlier invention date. Enzo fails to show that the inventors were in
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`“possession” of the claimed invention at the time of filing of the January 1983
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`application. Thus, VPK is § 102(b) prior art. Even if the Board finds that the
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`claims are entitled to the 1983 filing date, VPK is § 102(a) prior art because Enzo
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`has not established that the claimed invention was reduced to practice before
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`VPK’s publication date.
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`1.
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`The 1983 application fails to comply with the written
`description requirement.
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`To satisfy the written description requirement, Enzo must show that it had
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`“possession” of the genus of non-porous solid supports at the time of filing of the
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`1983 application. Enzo primarily argues that the 1983 application discloses a
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`sufficient number of species to satisfy the written description requirement for the
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`genus of all “non-porous solid supports.” Response, 34-37.
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`But the proper inquiry for “possession” here is not whether the earlier
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`application disclosed an adequate number of species; rather, it is whether the 1983
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`application described the later-claimed “non-porous solid support” limitation as an
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`“important defining quality” of the invention. See Purdue Pharma L.P. v. Faulding
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`Inc., 230 F.3d 1320, 1327 (Fed. Cir. 2013). The 1983 application fails to convey to
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`a POSITA that the inventors were in possession of “non-porous solid supports” as
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`an important aspect of their invention.
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`The 1983 application does not use the term “non-porous,” and fails to
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`discuss any significance of immobilizing nucleic acids on “non-porous” substrates.
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`Petition, 42. In fact, the 1983 application shows immobilization of nucleic acids to
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`many solid supports that may be porous or non-porous. Ex.1004, 24:14-22; 30:5-7;
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`102-103: original claims 45, 46, 47. In a similar situation, the inventors broadly
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`disclosed analogs of rapamycin, but claimed a narrower sub-genus. Boston
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`Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353, 1367 (Fed. Cir. 2011).
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`Nothing in the patent-at-issue indicated that the sub-genus was “of special
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`interest,” and given the lack of “blaze marks” identifying the sub-genus, the
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`Federal Circuit found that “no reasonable juror could determine that the
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`specification ‘reasonably conveys to persons skilled in the art that the inventor had
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`possession’ of the claimed sub-genus.” Id.,1367-68.
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`Here, the 1983 application fails to indicate that the “non-porous”
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`characteristic of the disclosed solid supports was of any “special interest” and
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`provides no “blaze marks.” Thus, the 1983 application fails to convey that the
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`inventors considered “non-porous” solid supports as their invention.
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`Therefore, the challenged claims are not entitled to the filing date of the
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`1983 application, and VPK is § 102(b) prior art.
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`2.
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`No reduction to practice before VPK’s publication date.
`a.
`To establish actual reduction to practice, “an inventor must prove that he
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`Legal standard for actual reduction to practice.
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`constructed his claimed invention and that it would work for its intended purpose.”
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`Mazzari v. Rogan, 323 F.3d 1000, 1005 (Fed. Cir. 2003). The patent owner must
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`also establish the construction of an embodiment or performance of a process that
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`met every claim limitation. Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1169
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`(Fed. Cir. 2006). An “unwitnessed notebook is insufficient on its own to support a
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`claim of reduction to practice.” Medichem, 437 F.3d at 1169-70 (citing Reese v.
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`Hurst, 661 F.2d 1222, 1232 (C.C.P.A. 1981) (“The inventors' notebooks are
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`accorded no more weight than the inventors’ testimony [], since they were not
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`witnessed or signed and were unseen by any witness until after this interference
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`was declared.”)).
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`b.
`Enzo’s exhibits fail to show reduction to practice.
`All of the challenged independent claims recite, inter alia, fixation or
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`immobilization of nucleic acid “in hybridizable form to [a] non-porous solid
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`support via [] one or more amine(s), hydroxyl(s) or epoxides(s).” Enzo did not
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`establish that this limitations was reduced to practice before VPK’s publication
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`date.
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`For this limitation, Enzo contends that documents of one of the named
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`inventors, Dr. Barbara Thalenfeld, (Exs. 2040, 2041) show binding of nucleic acids
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`in “hybridizable form” to plastic plates. Response, 46-49. Ex.2041 shows two
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`types of plates—one treated with PLL and the other left uncoated (“straight plate”).
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`Ex.2041, 1; Ex.1035, 80:12-81:25. Ex.2041 failed to specify which of those plates
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`was subjected to the experiments on the following pages. Ex.1035, 87:4-10. And
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`Ex. 2040 shows the purported hybridization experiments were conducted with
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`DNA bound directly to uncoated plates. Ex.2040, 2-3; Ex.1035, 72:9-73:14, 74:20-
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`23. In fact, Buck testified that that he could not read the results of the experiment
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`reported in Ex. 2041, and therefore he could not even confirm that it showed
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`hybridization. Ex.1035, 81:5-17.
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`Enzo also submits no evidence of hybridization for DNA bound via an
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`amine, a hydroxyl, or an epoxide hybridized. Thus, Exs. 2041 and 2040 fail to
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`show reduction to practice of ssDNA fixed in hybridizable form via “one or more
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`amine(s), hydroxyl(s) or epoxides(s).”
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`Also, Buck testified that that he could not read the results of the experiment
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`reported in Ex.2041, and therefore he could not even confirm that it showed
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`hybridization. Ex.1035, 81:5-17.
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`Although Enzo presents documents showing silanization of glass (Response,
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`44-45) to provide amines on the surface of the solid support, Enzo has not
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`established that nucleic acids were bound in “hybridizable form” to the silanized
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`glass.2
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`Although DNA bound to PLL would be inherently capable of hybridization,
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`actual reduction to practice cannot be based on inherency; rather Enzo must
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`provide proof that the invention “would work for its intended purpose.” See
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`2 Although Buck refers to some alleged experiments involving epoxides and epoxy
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`glue in his declaration (Ex.2042, 92-93), Enzo does not sufficiently discuss those
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`experiments in its Response and simply cites Buck’s declaration for support. This
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`constitutes an improper incorporation by reference and should not be considered.
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`See 37 C.F.R. § 42.6(a)(3).
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`16
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`Mazzari, 323 F.3d at 1005. “In addition, the inventor must contemporaneously
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`appreciate that the embodiment worked and that it met all the limitations of the
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`[claimed invention].” Cooper v. Goldfarb, 154 F.3d 1321, 1327 (Fed. Cir. 1998)
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`(citation omitted). Here, Enzo has provided no proof that the inventors were able to
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`test and “contemporaneously appreciate” that nucleic acids bound to PLL coated
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`plates were in “hybridizable form.”
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`Because Enzo presents no credible evidence showing that immobilization of
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`nucleic acids “in hybridizable form to [a] non-porous solid support via [] one or
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`more amine(s), hydroxyl(s) or epoxides(s)” was accomplished prior to VPK’s
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`publication date, Enzo cannot antedate VPK with respect to the challenged
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`independent claims and their dependents.3 Therefore, VPK is at least § 102(a) prior
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`art.
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`Moreover, Enzo has not shown that the covalent binding claims (dependent
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`claims 38, 78, and 218) were reduced to practice prior to VPK’s publication date.
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`Enzo relies on the covalent binding of gamma-aminopropyltriethoxysilane to the
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`hydroxyls on a glass surface. Response, 51; Ex.2042, ¶104. These claims,
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`3 Enzo has not presented evidence that claims 64, 101, 195, and 233 were reduced
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`to practice prior to VPK’s publication date. VPK is therefore § 102(a) prior art at
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`least for those claims.
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`17
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`however, require covalent binding of the nucleic acids to the non-porous solid
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`support (and not covalent binding of a surface treatment to the underlying
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`support—otherwise VPK would anticipate both noncovalent and convalent claims
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`because it uses the same chemistry). Therefore, Enzo has not established that the
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`subject matter of these claims was reduced to practice before the publication date
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`of VPK.
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`c.
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`Enzo’s lab notebooks are unreliable and not properly
`corroborated.
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`Enzo’s misstates the law that “[o]nly inventor testimony requires
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`corroboration; neither physical evidence nor documentary evidence requires
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`corroboration.” But the conception case that Enzo relies on—Price v. Symsek, 988
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`F.2d 1187 (Fed. Cir. 1991)— states that the content of the documentary evidence
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`does not require corroboration; it says nothing about the date of conception. This
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`was confirmed by the PTAB in Microsoft Corp. v. Surfcast, Inc., IPR2013-00292
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`(PTAB October 14, 2014) (finding that although content of a documentary
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`evidence for conception does not require corroboration, the date or origin of the
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`document requires corroboration to show earlier conception). Independent
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`corroboration also is required for reduction to practice dates.
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`Here, Enzo has presented unwitnessed notebooks of the inventors as proof
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`that the invention of the challenged claims was reduced to practice between
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`18
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`January and September of 1982. See Exs. 2037-2041; Ex.1036 (Weiner Tr.),
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`67:23-70:10, 92:7-93:23, 140:6-143:12. But an unwitnessed notebook is
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`insufficient on its own to support a claim of reduction to practice. See Reese, 661
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`F.2d at 1232; Medichem, 437 F.3d at 1172 (“As far as the corroborative value of
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`the inventors’ notebooks is concerned, they were not witnessed, and they do not
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`provide an ‘independent’ source of authority on the issue of reduction to
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`practice.”).
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`To corroborate the inventor notebooks, Enzo relies on the testimony of its
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`President and CFO, Mr. Barry Weiner. As evident from Mr. Weiner’s deposition
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`testimony, he has no independent knowledge of when the inventors’ had
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`successfully tested immobilization of nucleic acids in “hybridizable” form to non-
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`porous solid supports. See Ex.1036, 136:11-140:5 (testifying that the
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`immobilization and hybridization experiments were done sometime during the
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`1980-1984 timeframe and that he “cannot say that [he] was aware of the specific
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`date that the experiment was deemed to say [sic] success.”).
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`Moreover, Mr. Weiner testified that he did not have a scientific background
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`and he did not work in the lab with the inventors; any knowledge he has regarding
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`the claimed invention can be imputed to information received from the inventors.
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`Ex.1036, 19:13-21:23, 24:6-25. Therefore, he cannot independently corroborate the
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`19
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`date when the claimed invention was reduced to practice. See Medichem, 437 F.3d
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`at 1170 (“The requirement of independent knowledge remains key to the
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`corroboration inquiry.”). Because Enzo has failed to meet the independent
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`corroboration requirement, the unwitnessed notebooks should be accorded no
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`weight in determining reduction to practice.
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`d.
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`The challenged independent claims include indirect
`binding of nucleic acids to a non-porous solid support
`via a cell.
`The challenged independent claims do not require direct interaction between
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`nucleic acids and the “non-porous solid support.” In fact, claims 16, 222, and 230,
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`which depend from one or more of the challenged independent claims, specifically
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`recite that the “fixation or immobilization is not to a cell fixed in situ to said non-
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`porous solid support.” (Emphasis added.) Since the scope of an independent claim
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`must be broader than that of a dependent claim, the scope of the challenged
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`independent claims must include fixation or immobilization of nucleic acids via
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`cellular material. See, e.g., Arlington Industries, Inc. v. Bridgeport Fittings, Inc.,
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`632 F.3d 1246, 1249 (Fed. Cir. 2011) (relying on the doctrine of claim
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`differentiation, the Federal Circuit majority held that a disputed claim term in the
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`independent claim cannot be limited to a narrower limitation in a dependent
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`20
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`claim.); see also pre-AIA 35 U.S.C. § 112, ¶4 (“[A] claim in dependent form shall
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`… specify a further limitation of the subject matter claimed.”) (Emphasis added.)
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`Thus, the independent claims here cannot exclude fixation of a nucleic acid
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`through a cell fixed in situ to said non-porous solid support, because that would
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`limit the scope of those independent claims to the dependent claims recite that
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`limitation.
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`Moreover, during prosecution, Enzo amended the claims that later became
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`the challenged independent claims by deleting the limitation “fixation or
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`immobilization is not to a cell fixed in situ,” and adding that limitation to new
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`dependent claims 3288, 3294, and 3317, thus broadening the scope of the
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`independent claims to include fixation or immobilization via a cell. See Ex.2021 at
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`4-45 (showing claim amendments). Enzo also admitted during prosecution that
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`indirect fixation via a cell was within the scope of invention. Ex.1013, 94 (stating
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`that “indirect fixation techniques, such as in situ hybridization …, and direct
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`fixation techniques--are applicable, according to the specification, to fixing nucleic
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`acids to a non-porous solid support.”).
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`Indeed, there is no dispute that VPK discloses fixing DNA within a cell in
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`situ on a glass slide. See, e.g., Response at 59; Ex.2042, ¶204. Thus, VPK discloses
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`every limitation of the challenged independent claims.
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`21
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`e.
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`The nucleic acids bound to the glass slide of VPK are
`complementary to a nucleic acid sequence of interest.
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`VPK explicitly discloses in situ hybridization of immobilized human
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`ribosomal DNA in metaphase chromosomes to complementary 18S and 28S rRNA
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`probes to identify the DNA sequ