Beck Lin
`
`From:
`Sent:
`To:
`Cc:
`Subject:
`Attachments:
`
`Dear Karl and Becky,
`
`Kahn, Michael <kahnm@med.usc.edu>
`Thursday, April 12, 2012 2:11 PM
`Becky Lin; Karl Hermanns
`???
`Declaration regarding patents 13,194,428 and 13,172,315
`13172315_officeaction[1].pdf; Declaration of Michael Kahn Ph.D. 04.12.12.pdf
`
`Please find attached my further declaration in satisfaction of my duty to disclose information material to patentability in
`
`view of cases 13,194,428 and 13,172,315 under 37 C.F.R. 1.56. I am also attaching the highly relevant recent office
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`action for 13,172,315, which was not disclosed as part of the 13,194,428 case. The declaration and the recent office
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`action for the 13,172,315 case need to be disclosed to the patent office and the examiner prior to the issuance of the
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`13,194,428 case for which the issuance fees were paid on April 6th 2012.
`
`The present declaration should not be considered duplicative or cumulative relative to the prior DECLARATION OF DR.
`
`MICHAEL KAHN already of record in the present case (i.e., see item 19 under ”Non-Patent Literature Documents” in the
`present Applicants’ IDS). The current Declaration includes, inter alia, discussion of the alleged bases of support filed in a
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`Preliminary Amendment dated 29 July 2011 in the present 13/194,428 case, and additionally discusses the new matter
`
`rejection in a recent Office Action dated 27 September 2011, in a highly related (essentially identical) pending case
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`13/172,315 case attempting to claim the same compounds as presently claimed, and where the Office Action in the
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`13/172,315 case has not been made of record in the present case.
`
`Thank you for your attention to this matter. Please confirm. receipt ofthis email.
`
`Sincerely,
`
`Mike
`
`Michael Kahn, Ph.D.
`
`Professor of Biochemistry and Molecular Biology
`
`Provost’s Professor of Medicine and Pharmacy
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`Co—Chair, GI Oncology Program
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`

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`USC Norris Comprehensive Cancer Center
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`Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research
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`
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`

`

`
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Sung Hwan Moon, et al.
`29 July 2011
`13/194,428
`REVERSE-TURN MIMETICS AND METHOD RELATING THERETO
`Kahsay Habte
`1624
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`Applicants:
`Filing Date:
`Serial No.:
`For:
`Examiner:
`Art Unit:
`
`Commissioner for Patents
`P. O. Box 1450
`Alexandria, VA 22313-1450
`
`FURTHER DECLARATION OF DR. MICHAEL KAHN
`IN SATISFACTION OF DUTY TO DISCLOSE INFORMATION MATERIAL TO
`PATENTABILITY UNDER 37 C.F.R. § 1.56
`
`
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`Sir:
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`I, Dr. Michael Kahn, being duly sworn, say:
`
`I am an original joint inventor of the above-identified continuation patent
`1.
`application and very familiar with its originally-filed contents. I am aware that it discloses and
`claims particular novel genera and species of conformationally constrained compounds that
`mimic the secondary structure of reverse-turn regions of biologically active peptides and
`proteins.
`
`I am an internationally recognized chemist and scientist and expert in the field of
`2.
`reverse-turn mimetic structures/scaffolds, and am presently employed as Professor of
`Biochemistry and Molecular Biology, Professor of Pharmacology and Pharmaceuticals, and
`Provost Professor of Medicine and Pharmacology, 1425 San Pablo, ZNI-533, Los Angeles, CA
`90033. I received a B.A., Chemistry from Columbia University in 1978, and a Ph.D., Chemistry
`from Yale University in 1983. I am also a cofounder and outside board member of Prism
`BioLabs corporation of Yokohama, Japan.
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`I am an author or co-author of 95 peer-reviewed research articles, 11 book
`3.
`chapters, and an inventor on over 60 patents and patent applications (including the present
`application) (APPENDICES B and C), and my research has been presented at numerous national
`and international meetings. Many of these presentations have been given at the request of
`conference organizers for both educational workshops on discovery and development of reverse-
`turn mimetics and/or the results of my research. My curriculum vitae is attached hereto as
`APPENDIX A.
`
`In my capacity as a Ph.D.-level chemist and scientist, I am familiar with a broad
`4.
`spectrum of organic reverse-turn mimetic structures, and synthetic methods for preparing these
`compounds. As an inventor on numerous patents I am also generally familiar with the patent
`prosecution process, including the requirement for an inventor Declaration and the duty to
`disclose information that is material to patentability that runs to each inventor.
`
`As an initial matter, the present Declaration is not duplicative or cumulative
`5.
`relative of my prior Declaration that is already of record in the present case (i.e., see item 19
`under “Non-Patent Literature Documents” in the present Applicants’ IDS). The present
`Declaration includes, inter alia, discussion of the alleged bases of support filed in a Preliminary
`Amendment dated 29 July 2011 in the present 13/194,428 case, and additionally discusses the
`new matter rejection in a recent Office Action dated 27 September 2011, in a highly related
`(essentially identical) pending case 13/172,31 attempting to claim essentially the same
`compounds as presently claimed. Notably, the Office Action in the 13/172,315 case has not been
`made of record in the present case.
`
`In the present continuation application (13/194/428) prosecution, a Preliminary
`6.
`Amendment was filed on 29 July 2011, and an additional amendment on 28 March 2012, both of
`which introduce new matter into the claims. Specifically, while the original claims had no
`substituent at the 9-position of the pyradino[2,1-c]triazine ring, new claims 43-7,49, 50, 52 54-61
`were introduced for the first time by the Preliminary Amendments encompassing new
`compounds not disclosed or otherwise taught in the original specification, and having a
`“substituted or unsubstituted C1-7 alkyl” radical at the 9-position of pyradino[2,1-c]triazine ring
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`(amendment of 29 July 2011), or having “C1-7 alkyl” (amendment of 28 March 2012) in the
`context of, inter alia, an adjacent “Ra” bicyclic aryl group (e.g., see genus structure VI of claim
`43).
`As alleged “support” for claim 43, the preliminary amendment stated:
`
`
`“Support for claim 43 may be found in the present application, for example, as
`indicated below:
`• page 25, line 17 to page 26, line 5; page 26, lines 9-11 (describing compounds of
`formula (VI) and Ra);
`• page 26, lines 11-15 (describing Rb);
`• page 9, lines 15-17 (describing Rc, X1, X2, and X3);
`• Table 4 (containing compounds 69, 78, 80-83, and 111 with substituted or
`unsubstituted C1-7 alkyl at position 9);
`• Figure 1 and page 22, line 3 to page 23, line 4 (describing an exemplary synthetic
`scheme for making compounds of formula (IV) in which the first component piece is
`derived from glycine);’
`• page 24, line 17 to page 25, line 5 (describing synthesis of reverse-turn mimetics, e.g.,
`the compounds claimed in the present application, in more general terms and teaching
`that component pieces described in Figure 1 may be modified);
`• page 28, line 7 to page 29, line 2 (teaching that synthesis of a library of reverse-turn
`mimetics may be accomplished using known peptide synthesis techniques in
`combination with the component pieces);
`• Table 1 on pages 17 and 18 (listing amino acid side chain moieties, including
`substituted or unsubstituted alkyl);
`• page 18, lines 18-20 (classifying the amino acid side chain groups for alanine
`(methyl), valine (isopropyl), leucine (isobutyl) and isoleucine (sec-butyl) as "lower
`chain alkyl");
`• page 19, lines 1-6 (stating that "lower chain alkyl" includes C1-7 alkyl ).
`
`
`Support for "an unsubstituted bicyclic aryl group" as Ra in claim 44 may be
`found, for example, in Table 4 (see, compounds 5, 24, 33, 34, 39, 40, 70, 85, 89, 95,
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`114, 121, 122, 128, 135, 136, 141 and 142).
`Support for "a substituted bicyclic aryl group" as Ra claim 45 may be found, for
`example, in Table 4 (see, compounds 25, 56, 72, 74-76, 86-88, 91-94, 98-100, 104-107,
`112, 137, 138, 145-149, and 158).
`Support for claims 46 and 49 may be found as indicated above for claim 43.
`Support for claims 47 and 48 may be found in Table 2B (see, compounds 2927,
`2939, 2940, 2941, 2944, and 2974).
`Support for claims 50 and 51 may be found in Table 4 (see, compound 81).
`Support for claims 52 and 53 may be found in Table 4 (see, compound 82).
`Support for claims 54-61 may be found in original claim 12 of the present
`application and support for claims 44-47, 49, 50 and 52 as identified above.”
`
`(see Preliminary Amendment filed 29 July 2011).
`
`Significantly, however, none of the above alleged “support” adequately supports the
`newly-introduced claims in the amendments filed on 29 July 2011, and on 28 March 2012.
`
`Specifically, while the preliminary amendment filed on 29 July 2011 alleges that page 25,
`line 17 to page 26, line 5; page 26, lines 9-11 describe compounds of formula (VI) and Ra, what
`is actually and explicitly described on page 25 is formula (VI) as shown below, with only
`hydrogen at the 9-position of the pyradino[2,1-c]triazine ring, and moreover the description of
`“Ra” at page 26, describes “Ra” only in the context of a hydrogen at the 9-position (i.e.,
`formula (VI) “wherein Ra is….”):
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`Specifically, while the preliminary amendment alleges that page 26, lines 11-15 describes
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`Rb, these lines describe “Rb” only in the context of a hydrogen at the 9-position (i.e., formula
`(VI) “wherein Rb is….”).
`Specifically, while the preliminary amendment alleges that page 9, lines 15-17 describe
`Rc, X1, X2, and X3, page 9, lines 15-17 are actually part of the “Summary” and actually describe
`a subpart of a unrelated method, and have nothing to do with describing Rc, X1, X2, and X3. If
`the preliminary amendment intended to rather cite page 26, lines 15-17 then these lines describe
`“Rc,” “X1,” “X2,” and “X3” only in the context of a hydrogen at the 9-position (i.e., formula
`(VI) “wherein Rc is… and wherein X1, X2, and X3 may be….”). Moreover, there is no comment
`in the prosecution record by the Examiner regarding this erroneous alleged supporting citation.
`Specifically, while the preliminary amendment alleges that Table 4 shows compounds 69,
`78, 80-83, and 111 with substituted or unsubstituted C1-7 alkyl at position 9, this allegation is
`not true. Compounds 69, 78, 80, 83 and 111 all have a methyl group at the 9-position of the
`pyradino[2,1-c]triazine ring, and an adjacent monocyclic ring at “Ra.” Compound 81 has a O-
`formyl-hydroxymethyl group at the 9-position of the pyradino[2,1-c]triazine ring, and an
`adjacent monocyclic ring at “Ra.” Compound 82 has a hydroxymethyl group at the 9-position
`of the pyradino[2,1-c]triazine ring, and an adjacent monocyclic ring at “Ra.” Substitution at the
`position 9 with methyl, O-formyl-hydroxymethyl, or hydroxymethyl, does NOT support
`recitation of “C1-7 alkyl” at the 9-position of the pyradino[2,1-c]triazine ring in formula VI of
`claim 43. Moreover, even in this limited group of species having other than hydrogen at the 9-
`position, all have only an adjacent monocyclic ring at “Ra.” Therefore, the specification does
`NOT provide support for “C1-7 alkyl” at the 9-position with either monocyclic or bicyclic aryl
`groups at “Ra.” The specification supports only hydrogen at position 9 with an adjacent
`bicyclic ring.
`Specifically, while the preliminary amendment alleges that Figure 1 and page 22, line 3
`to page 23, line 4 describe an exemplary synthetic scheme for making compounds of formula
`(IV) in which the first component piece is derived from glycine, the Figure and description are
`limited to a solid phase synthetic scheme with hydrogen at the 9-position. Specifically, the
`description beginning at page 21, lines 13-14 recites “[t]hese compounds may be prepared by
`utilizing appropriate starting component materials (hereinafter referred to as ‘component
`pieces’).” The only antecedent basis for “these compounds” is in the preceding structural
`formulae (I)-(IV) on pages 14-21, which all have only hydrogen at the the 9-position of the
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`pyradino[2,1-c]triazine ring. There is absolutely no description whatsoever of formula (VI) as
`newly added with the preliminary amendment, and absolutely no description whatsoever of any
`synthetic scheme for making compounds of formula (VI) as presented in the preliminary
`amendment. Likewise, with respect to Figure 1, the “first component piece” (see below copied
`from Figure 1), is formed “by either reductive amination of H2N-R2 with CH(OR)2-CHO, or by a
`displacement reaction between H2N-R2 and CH(OR)2-CH2-LG (wherein LG refers to a leaving
`group, e.g., a halogen (Hal)( group).” In either event, the carbon that ends up at the 9-position of
`the pyradino[2,1-c]t riazine ring is NOT “derived from glycine as alleged in the preliminary
`amendment, and is rather derived as shown below, according to Figure 1. There is no teaching
`whatsoever that any part of the “first component piece” is derived from glycine or any
`other amino acid.
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`This carbon atom
`corresponds to the ultimate
`9-position of the
`pyradino[2,1-c]triazine ring
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`Moreover, the description of “amino acid side chain moiety” at page 17 line 11 through page 18,
`line 22, is given only to define particular embodiments of the “remainder of the molecule” as
`stated at page 17, lines 3-10. Significantly, any discussion of embodiments wherein specific R
`groups (e.g., R1, R2, R3…R9) may represent the “remainder of the compound” not only all relate
`to the defined R groups of formula (I) (which has no R group at the 9-position), but nowhere in
`the specification is there any description whatsoever of any teaching that the 9-position of
`the pyradino[2,1-c]triazine ring is derived from an amino acid side chain or derivative
`thereof. In fact, the specification, including the alleged “support” cited in the preliminary
`amendment, explicitly teaches against this, because the chemical synthetic teachings of the
`specification solely teach hydrogen at this position.
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`Specifically, while the preliminary amendment alleges that page 24, line 17 to page 25,
`line 5 describe synthesis of reverse-turn mimetics, e.g., the compounds claimed in the present
`application, in more general terms and teach that component pieces described in Figure 1 may be
`modified, there is NO teaching whatsoever that that the 9-position of the pyradino[2,1-
`c]triazine ring is other than hydrogen, or is derived from an amino acid side chain or
`derivative thereof. Moreover, the reference cited in the preliminary amendment to “with
`appropriate modifications to the component pieces” is explicitly in reference to the structures of
`formula (III) and (IV) (see page 25 at lines 3-5), both of which have only hydrogen at the 9-
`position of the pyradino[2,1-c]t riazine ring.
`Specifically, while the preliminary amendment alleges that page 28, line 7 to page 29,
`line 2 teaches that synthesis of a library of reverse-turn mimetics may be accomplished using
`known peptide synthesis techniques in combination with the component pieces, this has
`absolutely nothing to do with substitution at the 9-position of the pyradino[2,1-c]triazine ring,
`and rather simply teaches that “any amino acid sequence may be added to the N-terminal and/or
`C-terminal of the conformationally constrained reverse-turn mimetics (see page 28, lines 10-11),
`which relates to facilitating synthesis on a “solid support, and NOT to what is present at the 9-
`position of the pyradino[2,1-c]triazine ring. The example on page 28, line 16 through page 29,
`line 2, only discusses synthesizing a linear peptide on the solid support, adding a “previously
`synthesized reverse-turn mimetic structure as the next amino acid (via its N- or C-terminus, and
`not the 9-position ring carbon), and further addition of additional amino acids (via its N- or C-
`terminus. This teaching has nothing to do with substitution at the 9-position of the
`pyradino[2,1-c]triazine ring.
`Specifically, while the preliminary amendment alleges that Table 1 on pages 17 and 18
`listing amino acid side chain moieties, including substituted or unsubstituted alkyl, this teaching
`has nothing to do with substitution at the 9-position of the pyradino[2,1-c]triazine ring. As
`stated above, the description of “amino acid side chain moiety” at page 17 line 11 through page
`18, line 22, is given only to define particular embodiments of the “remainder of the molecule” as
`stated at page 17, lines 3-10, and any discussion of embodiments wherein specific R groups (e.g.,
`R1, R2, R3…R9) may represent the “remainder of the compound” not only all relate to the defined
`R groups of formula (I) (which has no R group at the 9-position), but nowhere in the
`specification is there any description whatsoever of any teaching that the 9-position of the
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`pyradino[2,1-c]triazine ring is derived from an amino acid side chain or derivative thereof.
`In fact, the specification, including the alleged “support” cited in the preliminary amendment,
`explicitly teaches against this, because the chemical synthetic teachings of the specification
`solely teach hydrogen at this position.
`Specifically, while the preliminary amendment alleges that page 18, lines 18-20
`classifyies the amino acid side chain groups for alanine (methyl), valine (isopropyl), leucine
`(isobutyl) and isoleucine (sec-butyl) as "lower chain alkyl", there is absolutely no teaching
`whatsoever of any teaching that the 9-position of the pyradino[2,1-c]triazine ring is derived
`from an amino acid side chain or derivative thereof.
`Specifically, while the preliminary amendment alleges that support for "an unsubstituted
`bicyclic aryl group" as Ra in claim 44 may be found, for example, in Table 4 (see compounds 5,
`24, 33, 34, 39, 40, 70, 85, 89, 95, 114, 121, 122, 128, 135, 136, 141 and 142), ALL of these
`compounds have hydrogen at the 9-position of the pyradino[2,1-c]triazine ring. Nowhere in
`the specification is there a single species described having other than hydrogen at the 9-position
`when there is a bicyclic group at “Ra.” This is not surprising given the steric constraints present
`in these “conformationally constrained reverse-turn mimetic structures” (see more detailed
`discussion of this point below).
`Specifically, while the preliminary amendment alleges that support for "a substituted
`bicyclic aryl group" as Ra claim 45 may be found, for example, in Table 4 (see, compounds 25,
`56, 72, 74-76, 86-88, 91-94, 98-100, 104-107, 112, 137, 138, 145-149, and 158), ALL of these
`compounds have hydrogen at the 9-position of the pyradino[2,1-c]t riazine ring. Nowhere
`in the specification is there a single species described having other than hydrogen at the 9-
`position when there is a bicyclic group at “Ra.” This is not surprising given the steric constraints
`present in these “conformationally constrained reverse-turn mimetic structures (see more detailed
`discussion of this point below).
`Specifically, while the preliminary amendment alleges that support for claims 46 and 49
`may be found as indicated above for claim 43, there is in fact NO support for claim 43 as
`discussed in detail above.
`Specifically, while the preliminary amendment alleges that support for claims 47 and 48
`may be found in Table 2B (see, compounds 2927, 2939, 2940, 2941, 2944, and 2974), these
`compounds do NOT support claims 47 and 48. Table 2B discloses a few compounds, (2927,
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`2939, 2940, 2941, 2944, and 2974) having a methyl group (not “Rd”) at the 9-position, but ALL
`such structures comprise an adjacent “Ra” radical that is a monocyclic moiety. Likewise,
`compounds 2942 and 2943, having –CH2OCHO and -CH2OH group at the 9-position,
`respectively, comprise an adjacent “Ra” radical that is a monocyclic moiety. A similar
`conclusion can be reached from looking at Table 4 (see compounds 69, 78, 80, 81, 82, 83, and
`111). The specification (including in view of the compounds in Table 2B), therefore, has neither
`description nor explanation about the substituent “Rd” as now claimed (there is no original
`teaching of “Rd is hydrogen and C1-7 alkyl”), and particularly there is no teaching of “Rd” (of
`any type) in the context of an adjacent “Ra” bicyclic aryl group.
`Specifically, while the preliminary amendment alleges that support for claims 50 and 51
`may be found in Table 4 (see, compound 81), compound 81 has a O-formyl-hydroxymethyl
`group at the 9-position of the pyradino[2,1-c]triazine ring, and an adjacent monocyclic ring at
`“Ra.” Substitution at the position 9 with methyl, O-formyl-hydroxymethyl does NOT support
`recitation of “C1-7 alkyl” at the 9-position of the pyradino[2,1-c]triazine ring.
`Specifically, while the preliminary amendment alleges that support for claims 52 and 53
`may be found in Table 4 (see, compound 82), compound 82 has a hydroxymethyl group at the
`9-position of the pyradino[2,1-c]triazine ring, and an adjacent monocyclic ring at “Ra.”
`Substitution at the position 9 with methyl, O-formyl-hydroxymethyl, or hydroxymethyl, does
`NOT support recitation of “C1-7 alkyl” at the 9-position of the pyradino[2,1-c]triazine ring in
`formula VI of claim 43. Moreover, even this limited number of species having other than
`hydrogen at the 9-position, all have only an adjacent monocyclic ring at “Ra.” Therefore, the
`specification does NOT provide support for C1-7 alkyl” at the 9-position with either monocyclic
`or bicyclic aryl groups at “Ra,” and the specification supports only hydrogen at position 9 with
`adjacent bicyclic.
`Specifically, while the preliminary amendment alleges that support for claims 54-61 may
`be found in original claim 12 of the present application and support for claims 44-47, 49, 50 and
`52 as identified above,” there is in fact no support for claim 43 as discussed in detail above
`because ALL of these claims depend, directly or indirectly from claim 43, and thus there is
`no support for claims 54-61 or 44-47, 49, 50 and 53.
`
`
`Additionally, in a Response and Amendment filed in this case (13/194,428) on 28 March
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`2012, claim 43 was amended to recite “C1-7 alkyl” in place of “substituted or unsubstituted C1-7
`alkyl”, and claims 47 and 58 were amended to “wherein the C1-7 alkyl is methyl” in place of
`“wherein the unsubstituted C1-7 alkyl is methyl.”
`In view of the above-described lack of support for even “C1-7 alkyl,” amending claim 43
`to recite “C1-7 alkyl” in place of “substituted or unsubstituted C1-7 alkyl” does NOT cure the
`deficiency of written description and enablement for claims as amended on 28 March 2012.
`Additionally, the argument regarding alkyl moieties defined by amino acid chains is at
`best applicable only to the R2 group in the synthetic scheme (i.e ., see Figure 1, and page 22 of
`the present 13/194,428 application, and including all the synthetic Examples 1, 2, 3, 4 and 5 (see
`pages 388-399) that all use bromoacetyl resin; and see also page 17, lines 1-2, stating that “one
`of more of R1, R2 and R4 represents an amino acid side chain”), and there is no variable group
`in the protected bromacetaldehyde (only H) of the scheme describe at page 22 or in the synthetic
`Examples. Therefore, the synthetic scheme in the present 13/194,428 application (as was
`deemed to be true in the related 13/172,315 case discussed above) is limited to H at the 9-
`position of the pyradino[2,1-c]triazine ring, and in any regard, there is no written description for
`“C1-7 alkyl” as presently claimed in the 13/194,428 application.
`Additionally, the present case is a continuation of serial number 12/553,858, wherein
`claims identical to those presently sought were rejected (new matter) based on lack of written
`description.
`
`Moreover, in a recent Office Action dated 27 September 2011, in a highly related
`(essentially identical) pending case 13/172,315 case claiming the same compounds as presently
`claimed (see 13/172,315 formula (VI) genus structure below taken from analogous claim 43 of
`13/172,315 ) (Office Action attached hereto, and see discussion below under paragraphs 12-14),
`the Examiner rejected the claims for “new matter” (lack of written description):
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`In response to the Examiner’s new matter rejection in the related 13/172,315 case, the
`applicants recently submitted a Response with a Declaration of Dr. Chi-Ching Mak as alleged
`support of the rejected (new matter) claims. The Response states that:
`
`
`“[b]riefly, Dr. Mak reads the present application as:
`(a) illustrating synthesis of the claimed compounds using a first component piece
`that is a glycine equivalent (i.e., the amino acid side chain group is hydrogen), and
`exemplifying the same with a very large number of compounds having hydrogen at the 9-
`position;
`(b) teaching that compounds of formula (VI) may be made with modification to the
`component pieces;
`(c) exemplifying such modification with compounds made using a first component
`piece other than a glycine equivalent, of which Compounds Nos. 69, 78, 80, 83, and 111
`exemplify the embodiment wherein the first component piece is an alanine equivalent (i.e.,
`the amino acid side chain group - and thus the 9-position substituent of formula (VI) – is
`methyl); and
`(d) teaching that amino acid side chain groups include natural amino acid side chain
`groups, specifically hydrogen (glycine), methyl (alanine), isopropyl (valine), isobutyl
`(leucine) and sec-butyl (isoleucine); and further that a preferred amino acid side chain
`group is Cl-7 alkyl.”
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`(see page 10 of Response filed on 22 February 2012 in the related 13/172,315 case).
`
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`However, as discussed in detail in the instant Declaration, there is absolutely no support
`for these urged conclusions.
`Specifically, with respect to (a) above, and as discussed herein above in detail (see above
`discussion at page 5, line 19 to page 6, line 17 herein) there is no support for “Cl-7 alkyl”.
`Specifically, with respect to (b) above, as discussed herein above in detail (see above
`discussion at page 6, line 18 to page 7, line 4 herein) there is no support that any alleged
`“modifications” teach or support “Cl-7 alkyl”, and the specification recitation of “with appropriate
`modifications to the component pieces” is explicitly in reference to the structures of formula (III)
`and (IV) (see page 25 at lines 3-5), both of which have only hydrogen at the 9-position of the
`pyradino[2,1-c]t riazine ring.
`Specifically, with respect to (c) above, and as discussed herein above in detail (see above
`discussion at page 5, lines 6-18 herein) there is no support for “Cl-7 alkyl”. The specification does
`NOT provide support for C1-7 alkyl” at the 9-position with either monocyclic or bicyclic aryl
`groups at “Ra,” and he specification supports only hydrogen at position 9 with adjacent
`bicyclic.
`Likewise, with respect to (d) above, and as discussed herein above in detail (see above
`discussion at page 7, line 18 through page 8, line 4 herein), nowhere in the specification is there
`any description whatsoever of any teaching that the 9-position of the pyradino[2,1-
`c]triazine ring is derived from an amino acid side chain or derivative thereof
`In his Declaration, Dr. Mak states that he “believe[s] that the inventors of the present
`application had possession of the compounds and compositions claimed in the earliest priority
`application, US Application 10/803/179 (filed 3/27/04)” and further states that the priority
`applications exemplify over 3000 compounds, a significant portion of which are compounds with
`structures identical to formula (VI) except having a hydrogen at the 9-position, and that these
`applications also exemplify a number of compounds having substituents other than hydrogen at
`the 9 position and their inhibitory activities against SW480 cells…. Of these, compound Nos. 69,
`78, 80, 83 and 111 exemplify the embodiment wherein the 9 position is methyl [however, as
`discussed in detail in the instant Declaration, these five all have an adjacent monocyclic ring].
`Therefore, Dr. Mak states that of the over 3000 compounds claimed, only 5 (0.16%) are
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`representative of compounds described in formula (VI) except having a non-hydrogen (i.e.
`methyl group) at the 9-position. However, even with these 5 compounds having a methyl group,
`none of these compounds had a bicylcic aryl group having 8-11 members.
`Moreover, as an original inventor on the present application and on US Application
`10/803/179 (filed 3/27/04), it is my contention that such compounds with a non-hydrogen (i.e.
`methyl group) at the 9-position and a bicylcic aryl group having 8-11 members at the Ra position
`were not in possession of the inventors at the time of the filing of the application and furthermore
`were neither described or claimed in the instant application or in US Application 10/803/179
`(filed 3/27/04). Furthermore, compounds with a non-hydrogen (i.e. methyl group) at the 9-
`position and a bicylcic aryl group having 8-11 members at the Ra position could not be
`synthesized due to reasons of steric hindrance by the described solid phase synthetic procedure
`(as described in more detail herein below).
`Dr. Mak’s declaration also states that figure 1 of the specification illustrates the first
`component piece as a “glycine equivalent.” Even if one were to view the first component piece
`as comprising a “glycine equivalent”, there is no written description whatsoever for the use of
`any other first component piece other than having a hydrogen at the ultimate 9-position carbon—
`as described in detail herein above (see above discussion at page 5, line 19 to page 6, line 17
`herein), there is no support for “Cl-7 alkyl”.
`In section 15, Dr. Mak states that he “believe[s] the inventors invented compounds and
`compositions claimed having C1-7 alkyl (e.g., methyl) at the 9-position and had possession of
`compounds claimed in the present application when the earliest priority application (US
`Application No. 10/803,179) was filed.” However, while this statement may arguably be valid
`for compounds and compositions claimed having a methyl group at the 9-position and a
`monocyclic aryl group at Ra (e.g., as in compounds 69, 78, 80, 83 and 111), there is NO
`support for C1-7 alkyl at the 9-position with either adjacent monocyclic or adjacent bicyclic rings,
`and as an original inventor I herein declare that no compounds or compositions existed having
`C1-7 alkyl (e.g., methyl) at the 9 position and a bicylcic aryl group at Ra and that there was no
`possession of compounds claimed in the present application when the earliest priority application
`(US Application no. 10/803,179) was filed, nor was there written description disclosed that could
`have provide compounds of this type.
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`Specifically, in 13/194,428 there is:
`7.
`(1) no written descriptive support in the original specification for an “Rd” group (wherein
`“Rd” recites hydrogen or C1-7 alkyl) as added and claimed by the 29 July 2011 Preliminary
`Amendment, and in the 28 March 2012 Amendment( further amended to recite “C1-7 alkyl”);
`(2) no enabling synthetic methods in the original specification that would reasonably
`teach one skilled in the art to synthesize compounds that contain such an “Rd” group, methyl or
`otherwise, regardless of what the “Ra” group is;
`(3) no written descriptive support in the specification for an “Rd” group (wherein “Rd”
`recites hydrogen or C1-6 alkyl or C1-7 alkyl) in the context of an adjacent “Ra” bicyclic moiety;
`(4) no enabling synthetic methods in the original specification that would reasonably
`teach one skilled in the art to synthesize compounds that contain such an “Rd” group, methyl or
`otherwise, in the context of an adjacent “Ra” bicyclic moiety; and
`(5) no enabling disclosure for the alleged stereochemistry at the 9-position of
`pyradino[2,1-c]triazine ring of any of the compounds of the Tables .
`
`With respect to (1) and (3) above, the only groups disclosed at the 9-position of
`pyradino[2,1-c]triazine ring are methyl, –CH2OCHO and -CH2OH. The presently recited “C1-7
`alkyl” is thus new matter