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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________
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`HOLOGIC, INC.,
`and BECTON, DICKINSON AND COMPANY,
`Petitioners
`
`v.
`
`ENZO LIFE SCIENCES, INC.
`Patent Owner
`
`____________
`
`Case No. IPR2016-00822
`U.S. Patent No. 7,064,197
`____________
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`
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`PETITIONERS’ REPLY
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`Table of Contents
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`PRELIMINARY STATEMENT ..................................................................... 1
`
`
`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. .................. 5
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`B.
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`Claims obvious based on Fish. .............................................................. 9
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`1.
`
`2.
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`Obviousness concerning sequence of interest. ........................... 9
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`Obvious to use Fish’s binding technique for RNA. .................. 11
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`Claims obvious based on Fish in view of Metzgar and Sato. ............. 11
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`Claims obvious based on Fish in view of Gilham. ............................. 12
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`Anticipation of challenged claims by VPK. ........................................ 14
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`C.
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`D.
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`E.
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`1.
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`2.
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`3.
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`4.
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`5.
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`Enzo cannot claim priority to the 1983 application
`because it fails to comply with the written description
`requirement. .............................................................................. 15
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`No reduction to practice before VPK’s publication date. ......... 16
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`VPK in view Metzgar provides an array of ssDNA. ................ 21
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`It would have been obvious to a POSITA that the
`hybridization procedure described in VPK could be
`performed on glass slides having wells or depressions as
`disclosed by Metzgar. ............................................................... 21
`
`The nucleic acids bound to the glass slide of VPK are
`complementary to a nucleic acid sequence of interest. ............. 22
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`F.
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`Obviousness based on Noyes, VPK, Metzgar and
`Ramachandran. .................................................................................... 23
`
`
`
`i
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`
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`1.
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`Nucleic acids bound using the Noyes binding chemistry
`would remain in hybridizable form. ......................................... 23
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`2. Motivation to combine Noyes and Ramachandran to
`covalently bind RNA in hybridizable form to the glass
`slides of VPK. ........................................................................... 24
`
`III. THE SECONDARY CONSIDERATIONS, IF ANY, FAIL TO
`OVERCOME THE EVIDENCE OF OBVIOUSNESS ................................ 25
`
`A.
`
`B.
`
`Enzo’s technical expert is not qualified to opine on secondary
`considerations. ..................................................................................... 25
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`Enzo has not established a nexus between the merits of the
`claimed invention and any secondary considerations. ........................ 26
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`IV. CONCLUSION .............................................................................................. 27
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`
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`ii
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`I.
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`
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`PRELIMINARY STATEMENT
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`Case No. IPR2016-00822
`U.S. Patent No. 7,064,197
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`The Board recognized in its Institution Decision that it is more likely than
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`not that the challenged claims are unpatentable based on the grounds presented in
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`Hologic’s Petition. Nothing in Enzo’s Patent Owner Response calls that into
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`question. The conclusory and unsupported arguments of Enzo’s technical expert,
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`Dr. Gregory Buck (“Buck”) fails to alter the Board’s reasoning in its Institution
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`Decision. The Board should issue a Final Written Decision canceling the
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`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 of
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`ssDNA to PLL-coated wells. Decision,11-12.
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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, 12. The Decision quotes the following supporting sentence from Fish:
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`“[t]his positive control for nuclease S1 activity suggests that single-stranded nucleic
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`acid, bound to PLL treated plastic, remains susceptible to the hydrolytic activity of
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`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, 4-5; Ex.2142, ¶73. Enzo first argues that prior
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`hybridization methods involved ssDNA bound to porous materials or cells bound
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`to nonporous materials. As a consequence, Enzo argues that a POSITA would not
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`expect ssDNA to bind to PLL-coated polyvinyl plates. Response, 4-5; Ex.2142,
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`¶74. Enzo’s alleged state of the art, which did not address PLL binding to nucleic
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`acids, sheds no light on what the Fish authors knew about binding ssDNA to PLL-
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`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,4.
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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.2142, ¶76. But both ssDNA and dsDNA have
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`negatively-charged backbones, which allow them to bind to positively-charged
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`PLL-coated wells. Ex.1002, ¶45. Thus, if dsDNA binds to PLL-coated plates, there
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`is no reason to doubt that ssDNA would too. Id.
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`Enzo argues that antibody binding in Fish could only detect dsDNA, not
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`ssDNA, because Fish was designing an assay to detect antibodies that bound to
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`dsDNA, not ssDNA. Response, 5-6, 8. Fish’s goal was designing an assay for
`
`detecting antibodies that bind to dsDNA as Enzo argues. However, to achieve that
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`goal, the experiments depicted in Figs. 1, 3-4 used antibodies that bind to ssDNA.
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`(See testimony of Petitioners’ expert concerning detection of antibodies that bind
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`to ssDNA: Ex.2117, 114:14-23; 124:18-125:4; 125:10-18.) Fig. 1 used ssDNA
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`antibody binding as a positive control to assess the purity of the dsDNA to be used
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`in the anti-dsDNA assay. Ex.2142, ¶79; Ex.1006, 538, right col., ¶1. Figs. 3-4
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`assessed “[a]nti-ssDNA activity in patient and normal sera.” Ex.1002, ¶49;
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`Ex.1006, 540-541, Fig. 3-4 figure legends. That assessment showed that anti-
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`ssDNA antibodies bound to ssDNA in normal sera with too much frequency—
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`informing Fish that “binding to this type of single-stranded nucleic acid therefore
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`appears to have no 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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`without any ssDNA bound to them. Ex.2142, ¶¶85, 90-91. But Fish optimized
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`conditions to alleviate such background by adding a solution of BGG and BSA to
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`the wells to block non-specific binding. Ex.1002, ¶¶49-50; Ex.1035, 119:1-7;
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`122:20-123:5. Fish also included negative control wells not treated with DNA
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`(DNA-) to subtract out background signal from the results obtained with DNA
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`treated wells (DNA+). Ex.2142, ¶84; Ex.1035, 27:22-128:2. Thus, the positive
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`signals attributed to antibodies binding to immobilized ssDNA in Figs. 1, 3-4
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`already had background signal subtracted out. Id.
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`Petitioners’ expert, Dr. Nelson (hereinafter, “Nelson”) never agreed that the
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`results in the figures could have been due to background, and testified that the
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`optimized conditions suggest otherwise. Ex.1035, 88:1-16; 89:6-17, 120:13-18.
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`Also, Nelson’s agreement that background signal occurred in some of the DNA-
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`wells (Response, 7) does not indicate Fish’s experiments were flawed, because the
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`signal from the DNA- wells was subtracted from the signals in the DNA+ wells
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`(discussed above).
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`Finally, the Fig. 1 confirms that ssDNA was bound because S1 nuclease did
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`not digest the dsDNA. Decision, 11, 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 presented facts showing that the ssDNA that was bound to the
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`PLL-coated wells in Fish necessarily was “in hybridizable form.” And based on
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`those facts, Hologic explained why Fish’s bound ssDNA was in hybridizable form.
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`Petition, 22-27. The Decision agreed. Contrary to Enzo’s argument, the claim term
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`“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, 10. But the articles Buck cites discuss
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`slowing down —not preventing—the rate of hybridization. Ex.2142, ¶95, citing
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`Exs. 2112, 2113; 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.2142, ¶238. 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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`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 ¶238 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, 64:9-14; 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 in order for the bound ssDNA to be capable of
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`hybridizing. Enzo presents no facts suggesting how those factors could prevent
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`ssDNA, bound to the PLL-coated surface in Fish, from hybridizing under
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`appropriate conditions.
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`Nelson explained why Diehl (Ex.1021) provides additional confirmation that
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`ssDNA, bound to a PLL-coated wells in Fish, would be in hybridizable form.
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`Ex.1002, ¶¶55-61. Enzo first 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. Many of Enzo’s arguments focus on possible differences
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`in binding of ssDNA to a solid support, but Fish showed that ssDNA bound to the
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`PLL-coated wells. Enzo also argues that several factors could impact hybridization
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`capability, but offers no facts to support those positions. Ex.2042, ¶¶107, 114.1
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`1 See Ex. 1037 addressing Enzo’s concern about Ex.1032.
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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.2142, ¶¶107, 114.
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`Enzo also focuses on hybridization conditions, even though its claims lack
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`such a requirement, which the Decision noted. Response, 14-15, 17.
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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, Nelson testified that nucleic acid length could change
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`the conditions used for hybridization, “but no, it doesn’t alter the ability to
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`hybridize.” Ex.2117, 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, 16. 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 additional UV cross-linking, if anything, more likely would
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`prevent hybridization than PLL binding alone. Ex.1002, ¶61. Enzo offers no
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`evidence or reasoning to counter that testimony. Enzo also fails to explain why
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`betaine would impact bound ssDNA’s ability to hybridize.
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`Fish discloses an array of single-stranded nucleic acids.
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`3.
`In support of its sole argument that Fish does not show an array of nucleic
`
`acids, Enzo contends that Fish fails to show ssDNA bound to wells. Specifically,
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`Enzo argues that Fish’s microtitration tray, by itself, does not constitute an orderly
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`grouping or arrangement of nucleic acids in the context of the ’197 patent.
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`Response, 20. For the reasons discussed above, in the Petition, and in the Decision,
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`Fish discloses ssDNA bound to wells. Accordingly, Fish discloses the “array”
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`claim limitation.
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`During the deposition, Buck seemed to indicate that there was more to his
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`argument than the absence of DNA in Fish’s wells. Based on his testimony,
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`however, Petitioners see no need to add anything more to their Reply to Enzo’s
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`Response.
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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, 23-24. Buck fails to explain what “art” he is basing his conclusion 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 would have been known to interact with PLL-coated material.
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`Ex. 1035:64:9-14; Ex.1002, ¶¶43, 52. Enzo offers no facts why such binding,
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`which leaves the bases available for hybridization, would have been inappropriate
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`for 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, 24. The Decision,
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`however, 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, 24. 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, 25-26. 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 Metzgar and Sato.
`Enzo erroneously argues that the Petition “relied exclusively on Fish” for the
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`limitations in claims 120 and 189, and that Fish does not disclose an array.
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`Response, 26-27. But see Petition, 35-36; Ex.1002, ¶83 (describing Metzgar’s glass
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`slide as having wells and depressions that can be treated with PLL, as taught by
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`Sato, and that nucleic acids can be bound on the PLL-treated glass slide of Metzgar
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`using Fish’s method). The Petition further provides a more than sufficient reason to
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`combine Fish with Metzgar and Sato—visualization of radioactive and
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`nonradioactive signals under a microscope. Id. Enzo replied by arguing, without
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`any reasoning or evidence, that a hybridization reaction could not be performed on
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`Metzgar’s slide because the liquid would drain out. Response, 28. But a POSITA
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`would have known that hybridization assays can be performed on flat glass slides.
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`In fact, VPK did that exact thing. Ex.1002, ¶¶96-97. Thus, a POSITA would have
`11
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`been clearly motivated to apply Fish’s binding method on Metzgar’s glass slide to
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`provide an “array” on a transparent surface.
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`Enzo also argues that Fish does not disclose the chemistry by which PLL
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`binds to the wells or by which nucleic acids bind to the PLL coating. Response, 29.
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`However, Sato shows that PLL can be used to coat glass, and the mechanism of
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`binding between PLL and nucleic acids was well known in the art. Ex.1002, ¶¶44-
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`45, 83; Ex.1035, 63:6-64:14.
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`For the reasons presented, the Board should dismiss Enzo’s unsupported
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`attorney argument concerning unspecified differences between Fish, Metzgar, and
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`Sato that attempts to raise doubts about the viability of the combination. Response,
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`30.
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`D. Claims obvious based on Fish in view of Gilham.
`Rather than address the clear explanation of the chemistry involved in
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`Gilham’s ssDNA attachment technique presented by Nelson, Enzo offers
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`inaccurate testimony of a witness who had difficulty understanding the involved
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`chemistry. Enzo argues that a POSITA would not have applied the Gilham
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`chemistry to non-porous solid supports, but again, offered no facts supporting that
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`conclusion. Response, 32; Ex.2042, ¶138. A POSITA would have known that
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`PLL-coated wells have amines on the surface, which are available for the Gilham
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`binding 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.2142, ¶153. When asked if he was aware of
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`any such 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, ¶152. 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.2142, ¶157;
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`Ex.2117, 157:16-158:6. And even if non-specific binding were an issue, Buck
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`testified that treatments to address that issue were well known. Ex.1035, 76:2-
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`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, 34; Ex.2142, ¶156. 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, 34. But instead, Nelson suggested
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`using the Fish PLL-coated wells to perform the Gilham covalent bonding for
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`ssDNA hybridization assays. Ex.1002, ¶83; Ex.2017, 192:6-13.
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`E. 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 the January 1983 filing date of the earliest priority
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`application, and that the claims are entitled to an even earlier invention date. Enzo
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`fails to show that the inventors were in “possession” of the claimed invention at the
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`time of filing of the January 1983 application. Thus, VPK is § 102(b) prior art.
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`Even if the Board finds that the claims are entitled to the 1983 filing date, VPK is
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`§ 102(a) prior art because Enzo has not established that the invention of the claims
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`was reduced to practice before VPK’s publication date.
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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.
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`To satisfy the written description requirement, Enzo must show that it had
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`“possession” of the broad genus of non-porous solid supports at the time of filing
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`of the 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 a
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`later-claimed genus of all “non-porous solid supports.” Response, 37-40.
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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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`Case No. IPR2016-00822
`U.S. Patent No. 7,064,197
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`Nothing in the patent-at-issue indicated that the subgenus was “of special interest,”
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`and given the lack of “blaze marks” identifying the sub-genus, the Federal Circuit
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`found that “no reasonable juror could determine that the specification ‘reasonably
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`conveys to persons skilled in the art that the inventor had possession’ of the
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`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 limitation of the claim. Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157,
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`1169 (Fed. Cir. 2006). An unwitnessed notebook is insufficient on its own to
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`support a claim of reduction to practice. Medichem, 437 F.3d at 1169-70 (citing
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`Case No. IPR2016-00822
`U.S. Patent No. 7,064,197
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`Reese v. Hurst, 661 F.2d 1222, 1232 (C.C.P.A. 1981) (“The inventors' notebooks
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`are 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. Enzo has not established that this limitation of the independent claims was
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`reduced to practice prior to VPK’s publication date.
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`Specifically, Enzo has presented no evidence showing that “hybridization”
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`of nucleic acids was actually achieved on a non-porous solid support between
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`January and September of 1982. The Response at pages 49-53 merely provides
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`some experimental conditions for hybridization—no data or result showing
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`actually hybridization has been presented. See, e.g., Response, 51 (citing to Ex.
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`2140, p.3, which states that the reported experiment demonstrates the “feasibility
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`of in vitro hybridization,” but does not provide any results showing hybridization).
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`Buck further testified that he could not read the results of the experiment reported
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`in Ex. 2141 (Response, 49-50) and therefore could not confirm that it showed
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`hybridization. Ex. 1035, 81:5-17. Similarly, the experiments reported in Exs. 2137
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`Case No. IPR2016-00822
`U.S. Patent No. 7,064,197
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`and 2138 (Response, 52-53) show nucleic acid binding experiments; no
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`hybridization results are reported.
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`Although DNA bound to PLL, silanized glass, or other solid supports may
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`inherently be capable of hybridization, to establish actual reduction to practice,
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`however, Enzo cannot rely on inherency and must provide proof that the invention
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`“worked for its intended purpose.” See Mazzari, 323 F.3d at 1005. “In addition, the
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`inventor must contemporaneously appreciate that the embodiment worked and that
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`it met all the limitations of the [claimed invention].” Cooper v. Goldfarb, 154 F.3d
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`1321, 1327 (Fed. Cir. 1998) (citation omitted). Here, Enzo has provided no proof
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`that the inventors were able to test and “contemporaneously appreciate” that
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`nucleic acids bound to non-porous solid supports 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. Therefore, VPK is at least a § 102(a)
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`prior art to the challenged claims.
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`c.
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`Case No. IPR2016-00822
`U.S. Patent No. 7,064,197
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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.” Response, 43. But the conception case that Enzo relies on—Price
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`v. Symsek, 988 F.2d 1187 (Fed. Cir. 1991)— states that the content of the
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`documentary evidence does not require corroboration; it says nothing about the
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`date of conception. This was confirmed by the Board in Microsoft Corp. v.
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`Surfcast, Inc., IPR2013-00292 (PTAB October 14, 2014) (finding that although
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`content of a documentary evidence for conception does not require corroboration,
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`the date or origin of the document requires corroboration to show earlier
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`conception). Independent corroboration also is required for reduction to practice
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`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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`January and September of 1982. See Exs. 2137-2141; Ex.1036, 67:23-70:10, 92:7-
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`93:23, 140:6-143:13. But an unwitnessed notebook is insufficient on its own to
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`support a claim of reduction to practice. See Reese, 661 F.2d at 1232; Medichem,
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`437 F.3d at 1172 (“As far as the corroborative value of the inventors’ notebooks is
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`concerned, they were not witnessed, and they do not provide an ‘independent’
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`Case No. IPR2016-00822
`U.S. Patent No. 7,064,197
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`source of authority on the issue of reduction to 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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`date when the claimed invention was reduced to practice. See Medichem, 437 F.3d
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`at 1171 (“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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`Case No. IPR2016-00822
`U.S. Patent No. 7,064,197
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`VPK in view Metzgar provides an array of ssDNA.
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`3.
`Metzgar discloses a microscope slide made of glass and having “depressions
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`or wells on the top surface thereof.” Ex. 1009, Abstract; 2:28-30; Figure 1. As
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`discussed in the Petition, it would have been obvious to a POSITA that VPK’s
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`method of immobilization of metaphase chromosomes can be performed on the
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`“depressions or wells” of Metzgar’s glass slide to analyze multiple samples
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`simultaneously on the same slide. Petition, 45-46. The glass slide of Metzgar is
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`thus an “array,” as recited in the challenged independent claims, because the
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`“depressions or wells” on Metzgar’s slide allow an orderly grouping or
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`arrangement of nucleic acids, such as the metaphase chromosomes of VPK, bound
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`to the surface thereof. Ex. 1002, ¶99.
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`4.
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`It would have been obvious to a POSITA that the
`hybridization procedure described in VPK could be
`performed on glass slides having wells or depressions as
`disclosed by Metzgar.
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`Enzo argues that a PO
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