`
`UNITED STATES DEPARTl\IENT OF (‘.OMMER(‘.E
`United Slates Patent and Trademark Ofl'Ice
`Addiess: COMMISSIONER FOR PATENTS
`H0‘ Box [-850
`Alexandria. Virginia ZZ3l3~l-150
`\V H W .|IbpI0,g\)\
`
`APPLICATION NO.
`
`HLING DA'I'l:'
`
`l"'IRS’I' NAMED INVENIUR
`
`A'I"IOKNl:’Y DOCl(li'I' NO‘
`
`CONI"lRl\vIA'I'l0N NO.
`
`95/000.276
`
`07/09/2007
`
`6924261
`
`1 1767- 104-999
`
`2035
`
`M7505
`7590
`u 1/zsrzu I 3
`Womble Carlyle Sandridge & Rice, LLP
`Attn: IP Docketing
`PO. Box 7037
`Atlanta, GA 305374037
`
`,
`
`TURNER. SHARON L
`
`I
`
`I
`399]
`
`PWMWR
`
`MAIL DATE
`
`1 1/25/2013
`
`DELIVERY MODE
`
`PAPER
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`"UL-9°-A <R'-T 04/0”
`
`SANOFI-AVENTIS Exhibit 1051 - Page i
`IPR for Patent No. 8,445,647
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`CONJUCHEM, LLC
`Requester and Cross-Appellant
`
`v.
`
`AMYLIN PHARMACEUTICALS, INC.
`Patent Owner and Appellant
`
`Appeal2013-004331
`Inter Partes Reexamination Control 95/000,276
`U.S. Patent 6,924,264 Bl
`Technology Center 3900
`
`Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and
`JEFFREY B. ROBERTSON, Administrative Patent Judges.
`
`LEBOVITZ, Administrative Patent Judge.
`
`DECISION ON APPEAL
`
`This is a decision on the appeal by the Patent Owner from the Patent
`
`Examiner's decision to reject pending claims 24 and 26-36 in the above(cid:173)
`
`identified inter partes reexamination ofU.S. Patent No. 6,924,264 Bl. The
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`SANOFI-AVENTIS Exhibit 1051 - Page 1
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`IPR for Patent No. 8,445,647
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`
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`Appeal2013-004331
`Inter Partes Reexamination Control 95/000,27 6
`U.S. Patent 6,924,264 B1
`
`Board's jurisdiction for this appeal is under 35 U.S. C.§§ 6(b), 134, and 315.
`
`We affirm-in-part.
`
`I. BACKGROUND
`
`The patent in dispute in this appeal is U.S. Patent No. 6,924,264 B1,
`
`issued August 2, 2005 ("the '264 patent"). The Patent Owner ("PO") and
`
`Real Party in Interest is Amylin Pharmaceuticals, Inc. (PO Appeal Br. 1,
`
`dated February 15, 2012). A request for inter parte reexamination ofthe
`
`'264 patent was made on July 9, 2007 by third party requester Conjuchem
`
`Biotechnologies Inc.
`
`Claims 24 and 26-36 are pending and stand rejected by the Examiner.
`
`Claims 24 and 26-36 are not original claims but were added by amendment
`
`during the reexamination proceeding. Patent Owner appealed all the
`
`rejections.
`
`A Respondent Brief (March 15, 2012) and Cross-Appeal (February
`
`15, 2012) were filed on behalfofConjuChem, LLC, located at 11755
`
`Wilshire Blvd., Suite 2000, Los Angeles, CA 92005 who was listed as the
`
`Third Party Requestor and real party in interest in the respective briefs.
`
`However, the Third Party Requestor that filed the original Request for
`
`Reexamination leading to this appeal is ConjuChem Biotechnologies Inc.,
`
`located at 225, President-Kennedy Avenue, Montreal, QC H2X3Y8. The
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`parties therefore appear to be different. There does not appear to be any
`
`documentation in the record before us to indicate how, when, and why the
`
`real party in interest, or a person in privity thereto, may have changed since
`
`the filing of the Request. There also does not appear to be a change in
`
`2
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`Appeal2013-004331
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`correspondence or an appointment of power attorney to the attorney who
`
`filed the Respondent and Cross-Appeal briefs.
`
`An Order To Show Cause was mailed on October 18, 2013 giving the
`
`Requester two weeks to clarify the discrepancy between the real party in
`
`interest identified in the request for inter partes reexamination and the real
`
`party in interest set forth in Requester's Respondent brief. Otherwise, the
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`cross-appeal would be dismissed. The attorney who filed the Respondent
`
`Brief and Cross-Appeal was contacted by the PTAB on October 31, 2013,
`
`but she informed the PTAB that she has not been involved with the case for
`
`over a year. No response to the Order To Show Cause was received.
`
`Accordingly, as the party filing the Respondent Brief and Cross-Appeal is
`
`unauthorized, the Cross-Appeal is dismissed and consideration will not be
`
`given to the Respondent Brief to Patent Owner's Appeal. See 37 C.P.R.§§
`
`41.60, 1.915(b)(8), and 1.957(a).
`
`Claimed subject mater
`
`The claimed subject matter relates to exendin-4 conjugated to albumin
`
`or PEG. Exendin-4 is a known peptide found in the salivary secretions of
`
`the Gila monster ('264 patent, col. 1, ll. 34-48). Exendin-4 is related to
`
`members ofthe glucagon-like peptide (GLP) family (id. at col. 1, ll. 49-54),
`
`such as GLP-1. Exendin-4 was known to have an insulinotropic effect in
`
`stimulating insulin secretion from pancreas cells (id. at col. 1, 11. 54-56) and
`
`to be useful for treating diabetes (id. at col. 2, 11. 53-56). Exendin-4 was also
`
`reported to have a longer duration of action than GLP-1 (id. at col. 2, ll. 47-
`
`51 ). Exendin-4 and its analogs were known prior to the filing date of the
`
`3
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`'264 patent (id. at col. 3, 11. 13-28). The patent describes conjugating
`
`Exendin-4 to PEG or albumin (id. at col. 4, ll. 36-57; col. 24, ll. 58-65).
`
`Such conjugates are described by the '264 patent as having a kidney
`
`clearance less than unmodified exendin-4 (id. at col. 4, 11. 65-67; col. 24, ll.
`
`58-65; col. 31 ).
`
`Claims 24 and 26 are representative of the appealed claims and read
`
`as follows:
`
`24. A pharmaceutical composition for use in humans
`comprising a pharmaceutically acceptable carrier and a
`therapeutically effective amount of exendin-4 or an agonist
`analog of exendin-4 linked through the C-terminal amino acid
`to one polymer selected from the group consisting of
`polyethylene glycol and albumin.
`
`26. The pharmaceutical composition of claim 24, wherein
`the polymer is albumin.
`
`Rejections
`
`The claims stand rejected by the Examiner as follows (PO Appeal
`
`Br.):l
`
`A. Claims 24 and 26-36 under 35 U.S.C. § 103(a) as obvious in view
`of Eng2 in combination with Drucker III, 3 Davis, 4 Poznansky I ( 1984 ), 5
`Gombotz, 6 Shearwater,7 or Poznansky II (1988). 8
`
`1 Rejections A through D were listed by Patent Owner as rejecting claim 25.
`However, claim 25 is canceled.
`2 Eng, US 5,424,286, issued June 13, 1995.
`3 Drucker, WO 98/52600, published November 26, 1998.
`4 Davis et al, Reductions of Immunogenicity and Extension of Circulating
`Half-Life of Pep tides and Proteins, in Peptide and Protein Drug Delivery
`831-864 (Vincent H. L. Lee ed., 1991).
`
`4
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`SANOFI-AVENTIS Exhibit 1051 - Page 4
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`B. Claims 24 and 26-36 under 35 U.S.C. § 103(a) as obvious in view
`
`of Eng in combination with Knudsen II '872, Davis, Poznansky I (1984),
`
`Gombotz, Shearwater, or Poznansky II (1988).
`
`C. Claims 24 and 26-36 under 35 U.S.C. § 103(a) as obvious in view
`of Eng in combination with Chang I, 9 Davis, Poznansky I (1984), Gombotz,
`
`Shearwater, or Poznansky II (1988).
`
`D. Claims 24 and 26-36 under 35 U.S.C. § 103(a) as obvious in view
`of Knudsen I '990 10 in combination with Davis, Poznansky I (1984),
`
`Gombotz, Shearwater, or Poznansky II (1988).
`
`E. Claims 24, 26-31, 35, and 36 under 35 U.S.C. § 103(a) as obvious
`in view of Syed 11 in combination with Eng or Knudsen I '990.
`
`F. Claims 24, 26, 27, and 29-36 under 35 U.S.C. § 103(a) as obvious
`in view of Eng, Chang II, 12 and Harlow and Lane. 13
`
`G. Claims 24, 26, 27, and 29-36 under 35 U.S.C. § 103(a) as obvious
`in view of Eng, Bernard, 14 and Harlow and Lane.
`
`5 Poznansky & Juliano, Biological Approaches to the Controlled Delivery of
`Drugs: A Critical Review, 36(4) Pharmacological Reviews, 277-336 (1984).
`6 Gombotz & Pettit, Biodegradable Polymers for Protein and Peptide Drug
`Delivery, 6 Bioconjugate Chern., 332-351 (1995).
`7 Shearwater Polymers, Inc., Polyethylene Glycol Derivatives (June 1983)
`8 Poznansky et al., Growth hormone-albumin conjugates: Reduced renal
`toxicity and altered plasma clearance, 239 (1) FEB, 18-22 (October 1988).
`9 Chang, US 5,149,782, issued September 22, 1992.
`10 Knudsen, US 7,226,990 B2, issued Jun. 5, 2007.
`11 Syed et al., Potent Antithrombin Activity and Delayed Clearance From the
`Circulation Characterize Recombinant Hirudin Genetically Fused to
`Albumin, 89(9) Blood, 3243-3252 (May 1, 1997).
`12 Chang, US 5,274,075, issued Dec. 28, 1993
`13 Harlow & Lane, Antibodies: A Laboratory Manual 55-137 (1988).
`
`5
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`H. Claims 24, 26, 27, and 29-36 under 35 U.S.C. § 103(a) as obvious
`in view ofEdwards 15 in combination with Chang II, Harlow and Lane, and
`
`Poznansky I (1984).
`
`I. Claims 24, 26, 27, and 29-36 under 35 U.S.C. § 103(a) as obvious
`
`in view of Edwards in combination with Bernard, and Harlow and Lane.
`
`1. REJECTIONS BASED ON KNUDSEN I '990
`
`Rejection D
`
`Claims 24 and 36-36 stand rejected under 35 U.S.C. § 103 as obvious
`
`in view of Knudsen I '990 in combination with Davis, Gombotz,
`
`Shearwater, Poznansky I (1984), or Poznansky II (1988).
`
`Knudsen I '990
`
`Findings ofFact
`
`KI1. Knudsen I '990 describes exendins which "are useful in
`
`treatment of diabetes mellitus (types I and II) and prevention of
`
`hyperglycaemia." (Col. 19, 11. 57-58.)
`
`KI2. Knudsen I '990 also describes truncated exendins disclosed in
`
`WO 9746584 which "[c]ompared with GLP-1 and the known exendins, ...
`
`14 Bernard et al, Synthesis of conjugates between luteinizing hormone
`releasing hormone (LH-RH) and N-acetyl-muramyl-L-alanyl-D(cid:173)
`isoglutamine (MDP) models of totally synthetic vaccines, 29 Int. J. Pept.
`Protein Res. 455-463 (April4, 1987).
`15 Edwards et al, Glucagon-like peptide 1 has a physiological role in the
`control of postprandial glucose in humans: studies with the antagonist
`exendin 9-39, 48(1) Diabetes, 86-93, 1999.
`
`6
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`are more active (effective at lower doses), more stable to degradation and
`metabolism and have a longer lasting effect." (Col. 20, 11. 2-5.)
`
`KI3. However, Knudsen I 990 states "the high clearance limits the
`
`usefulness of these compounds, and thus there still is a need for
`improvements in this field." (Col. 20, 11. 6-8.) "Accordingly, it is one object
`
`of the present invention to provide derivatives of exendin and analogues
`
`thereof which have a protracted profile of action relative to native exendin."
`
`(!d. at col. 20, ll. 8-11.)
`
`KI4. To address this need, Knudsen I '990 teaches "an exendin
`
`derivative wherein at least one amino acid residue of the parent peptide has a
`
`lipophilic substituent attached." (Col. 20, ll. 12-14.)
`
`KI5. Knudsen I '990 describes preferred embodiments where the
`
`lipophilic constituent is attached to the N -terminal or C-terminal position,
`
`among other preferences (col. 20, ll. 17 -23).
`
`KI6. Knudsen I '990 teaches that its exendin derivatives modified as
`
`described above have a protracted profile of action (col. 22, ll. 34-43).
`
`Gombotz
`
`G 1. Gombotz discloses many clinically useful proteins and peptides
`
`that have been cloned and become commercially available (Gombotz, p.
`
`332, col. 2).
`
`G2. Gombotz teaches that efforts have been made to address some of
`
`the problems associated with proteins and peptides when administered
`
`therapeutically, including "research [which] has focused on the development
`
`7
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`of dosage forms which ... prolong the activity of the protein in vivo"
`
`(Gombotz, p. 332, col. 2).
`
`G3. Gombotz reviews "the various types of degradable polymers that
`
`have been used for the delivery of proteins and peptides." (Gombotz, p. 333,
`
`col. 2.)
`
`G4. Gombotz teaches protein-polymer conjugates, stating that there
`
`are many potential advantages, including altering the circulation
`
`pharmacokinetics, reducing renal clearance, and prolonging circulation half(cid:173)
`
`life (Gombotz, p. 344, col. 2).
`
`G5. Gombotz acknowledges that conjugating polymers to proteins
`
`can inactivate or alter protein activity (Gombotz, p. 344, col. 2).
`
`G6. Gombolz teaches:
`
`For many protein-polymer conjugation schemes, a balance
`between the desirable effects of conjugation and the loss of
`bioactivity must be established. Recently, investigators have
`attempted to avoid the problem of inactivation by the use of
`site-specific conjugation strategies.
`
`(Gombolz, p. 345, col. 1, first paragraph.) Site specific methods are
`
`described which utilize N-and C-terminal amino acids (id.)
`
`G7. Gombolz describes protein conjugates with albumin which
`
`showed increased stability and a significant increase in circulation half-life
`
`(Gombotz, p. 345, col. 1 ). "Albumin has been used as a pharmaceutical
`
`carrier to enhance circulation half-lives ofpeptides .... " (!d. at p. 345, cols.
`
`1-2).
`
`8
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`Poznansky I (1984)
`
`PII. Poznansky I (1984) teaches enzyme-albumin conjugates which
`
`stabilize the enzyme, mask antigenic determinants on the enzyme, and
`
`increase half-life (Poznansky I (1984), pp. 288 and 319, col. 1 ).
`
`PI2. Poznansky I (1984) teaches that a reactive group available for
`
`cross-linking is the "epsilon amino group of lysine residues." (Poznansky I
`
`(1984), p. 290, col. 1.)
`
`Poznansky II (1988)
`
`Pill. Poznansky II (1988) teaches that growth hormone (GH) is
`
`rapidly cleared by the kidney. "The rapid renal clearance of the peptide
`
`resulting in accumulation in the kidney will have to be resolved before
`
`growth hormone and other similar peptides are used effectively."
`
`(Poznansky II (1988), p. 18, col. 2).
`
`PII2. Poznansky II (1988) found that insulin conjugated to albumin
`
`retained its biological activity:
`
`We rationalize that if insulin can be conjugated to albumin
`while retaining its biological activity then the same should be
`true of a number of other small peptide hormones. Conjugation
`might therefore be used to dramatically alter the
`pharmacokinetics and potential usefulness of administered
`hormones such as growth hormone.
`(Poznansky II (1988), p. 19, col. 1)
`
`PII3. Poznansky II (1988) reported that growth hormone conjugated
`
`to albumin had an extended half-life and "clearly bypasses the kidneys and
`
`is cleared from the circulation largely by the liver." (Poznansky II (1988), p.
`
`19, col. 2). The data also showed that "that the conjugated GH retains much
`
`9
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`of the activity of the native hormone and may show increased potency in the
`
`conjugated form." (id. at pp. 19-20)
`
`PII4.
`
`This paper has demonstrated the possibility of altering
`small peptides by simple conjugation methods to larger
`molecules (such as homologous albumin) in the first instance to
`merely alter the pharmacokinetics by simply avoiding the
`kidneys. This has profound effects in terms of altered
`clearance, altered tissue deposition and reduced nephrotoxicity
`for OH and other bioactive peptides such as cytokines [citation
`omitted].
`(Poznansky II (1988), p. 21, col. 2.)
`
`PII5.
`
`The fact that so many of the activities of growth hormone are
`maintained is both fortuitous and of great interest; although the
`trial and error nature of the cross-linking procedure required to
`find conditions to retain hormone activity should be
`emphasized.
`(Poznansky II (1988), p. 21, col. 2.)
`
`PII6. Poznansky II (1988) reported that although the albumin-GH
`
`conjugate retained several biological activities, it did not stimulate growth in
`
`hypophysectomized rats (Poznansky II (1988), p. 21, col. 2.) Yet,
`
`Poznansky II (1988) stated that this fact "does not detract from the
`
`observation that small active peptides may be engineered in such a way as to
`
`enhance their suitability as therapeutic agents." (!d. at pp. 21-22.)
`
`Davis
`
`D 1. Davis teaches methods to improve the circulating half-life of
`
`peptide and proteins.
`
`10
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`D2. Davis teaches "[a]lbumin has also been conjugated to a variety of
`
`therapeutically useful proteins," disclosing that cross-linked albumin
`
`enzyme conjugates were made in 197 4, and describes a number of such
`
`examples (Davis, p. 838). Davis concluded that "[i]n all cases, the
`
`attachment of albumin resulted in an adduct with improved therapeutic
`
`characteristics." (!d.)
`
`D3. Davis summarizes results using albumin-protein conjugates,
`
`describing loss of activity in some cases, but with retention of biological
`
`activity when administered, and improved circulating half-life (Davis, p.
`
`839-840).
`
`Rejection
`
`The Examiner found that Knudsen I '990 teaches ex en din -4 and
`
`agonist analogs linked to lipophilic polymers via a C -terminal lysine residue,
`citing paragraphs 62, 484, 489, 500-504, 525, and 548-60 16 (RAN 11). The
`
`Examiner acknowledged that Knudsen I '990 does not teach that the
`
`polymer is PEG or albumin as required by claim 24 (id. ). However, the
`
`Examiner found that Davis, Gombotz, Shearwater, and Poznansky I and II
`
`teach peptide polymer conjugates with PEG and albumin for enhanced
`
`delivery (id. ), providing a reason to have made such modification to
`
`Knudsen I '990 (id.). The Examiner found that the "cited prior art
`
`establishes addition of C-terminal Lys for ease of conjugation and polymer
`
`carriers PEG and albumin as standard polymers to achieve enhanced drug
`
`delivery." (Jd.)
`
`16 The citations are to the published application which corresponds to the
`issued patent.
`
`11
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`Patent Owner
`
`First, Patent Owner contends that one of ordinary skill in the art
`
`would not have looked to extend the half-life of exendin-4 because it has a
`
`long half-life (Appeal Br. 6). To support this position, Patent Owner cited
`. 17
`G
`re1g:
`
`Grieg reports that the half-life of GLP-1 is "too short to achieve
`good 24-h metabolic control" but exendin -4 has a "prolonged
`effect of lowering blood glucose." Greig goes on to state that
`exendin-4 "could therefore be preferable to glucagon -like
`peptide- I as a long-term treatment for Type II diabetes."
`
`(PO Appeal Br. 6 (citation footnote omitted).)
`
`Second, Patent Owner argues that enzymatic degradation is the
`
`primary mode of clearance for all small human regulatory peptides, and
`
`"that on average, proteolytic degradation is over 7 fold more important than
`
`renal filtration for clearance of regulatory peptides." (PO Appeal Br. 7.)
`
`The inventors of the '264 patent discovered that exendin-
`4, unlike GLP-1 and the other regulatory peptides, is cleared
`exclusively (or nearly exclusively) by glomerular filtration, not
`enzymatic degradation. This was a surprising and unusual
`discovery, which is described in the '264 patent[.]
`
`(PO Appeal Br. 7.)
`
`Patent Owner contends that increasing the molecular size of peptides
`
`by conjugating them to polymers would be accomplished to prevent them
`
`being cleared by glomerular filtration, but since the extent to which exendins
`
`were cleared by glomerular filtration was not known, the skilled worker
`
`would not have reason to conjugate exendin to PEG or albumin (id. at 8).
`
`17 Greig et al., "Once Daily Injection ofExendin-4 to Diabetic Mice
`Achieves Long-Term Beneficial Effects of Blood Glucose Concentrations,"
`Diabetologia, 42, 45-50 (January 1999).
`
`12
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`Third, Patent Owner argues unpredictability. Patent Owner cites
`
`evidence from Gombotz that linking large molecular weight polymers to
`
`therapeutic proteins could adversely affect their activity, making it
`
`unpredictable (id. at 8-9). With respect to Poznansky II (1988), Patent
`
`Owner states that "[b ]y linking the growth hormone to albumin, they
`
`achieved a longer circulating half-life, but the growth hormone conjugate
`
`lost all therapeutic activity-it failed to promote any weight gain." (PO
`
`Appeal Br. 9.)
`
`Finally, Patent Owner contends that the claimed conjugate
`
`unexpectedly reduces the incidence of vomiting and nausea in Type 2
`
`Diabetic patients as compared to unconjugated exedin -4 (PO Appeal Br. 15)
`
`Discussion
`
`Claim 24 is drawn to exendin-4 conjugated to albumin. As discussed
`
`above, the Examiner found that one of ordinary skill in the art would have
`
`had reason to have made such conjugate to achieve enhanced delivery.
`
`Patent Owner contends that exendin-4 already had a long half-life and that it
`
`was known to have a prolonged glucose lowering effect. We have
`
`considered this evidence but do not find it persuasive.
`
`Firstly, Knudsen I '990 expressly teaches modifying exendins to
`
`"have a protracted profile of action relative to native exendin." (KI3 and
`
`KI6.) Thus, despite Patent Owner's argument to the contrary, Knudsen I
`
`'990 expressly recognized the need to improve the activity of an exendin by
`
`modifying it. And even if this teaching is not explicit, in view of the art(cid:173)
`
`recognized need to prolong the activity of therapeutic proteins as taught by
`
`13
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`Gombotz (G 1-G2), the skilled worker would have had reason to improve
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`exendin-4 even if it did have a "long" half-life because there is always a
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`desire by scientists to improve upon what is already known.
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`Despite Patent Owner's arguments and evidence about clearance of
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`exendin from plasma not being a consideration (PO Appeal Br. 7), Knudsen
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`I '990 mentions it as a concern (KI3). Patent Owner cited evidence that
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`clearance by kidney glomerular filtration would not have been a concern for
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`exendin-4 because proteolytic degradation was the main cause of clearance
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`of regulatory peptides from plasma (PO Appeal Br. 7; Declaration of
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`Andrew A. Young, M.D., Ph.D.; '264 patent at col. 31). Yet, Poznansky II
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`(1988) teaches that renal clearance was a concern for another small protein,
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`growth hormone (Pill and PII3). Gombolz also mentions renal clearance as
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`a reason for making peptide and protein conjugates (G4). Moreover,
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`Gombolz (G7), Poznansky I (1984) (PII), Poznansky II (1988) (PII3 and
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`PII4), and Davis (D1-D3) provide evidence that it was well-known to use
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`albumin to prolong the half-life of proteins, addressing the problem of "high
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`clearance" identified by Knudsen II '990 for exendin (KI3). Consequently,
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`there was more than sufficient reason for one of ordinary skill in the art to
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`have conjugated albumin to exendin-4.
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`We agree with Patent Owner that there was a degree of
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`unpredictability in whether conjugating albumin to exendin-4 would
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`improve its half-life without affecting its activity. However, there are
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`numerous examples in which conjugated albumin worked in imparting
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`stability and increasing half-life of proteins (G7, PII, PII2, PII3, and D2). In
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`fact, Davis stated that "[i]n all cases, the attachment of albumin resulted in
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`an adduct with improved therapeutic characteristics." (D2.)
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`As far as the loss of activity, there is evidence that conjugation to
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`albumin could result in loss of a protein's activity and in some cases did
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`(G5, G6, PII6, and D3). However, growth hormone did not lose all
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`"therapeutic activity" when conjugated to albumin, as alleged by Patent
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`Owner (see above). To the contrary, Poznansky II (1988) states that "that so
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`many of the activities of growth hormone are maintained is both fortuitous
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`and of great interest." (PII5.) And even though the growth hormone(cid:173)
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`albumin conjugate did not stimulate growth in hypophysectomized rats,
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`Poznansky II (1988) stated that this fact, nevertheless, "does not detract from
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`the observation that small active peptides may be engineered in such a way
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`as to enhance their suitability as therapeutic agents." (PII6.) Thus, despite
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`the recognition at the time of the invention that conjugation to a polymer like
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`albumin could adversely affect a protein's activity, it was still considered a
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`viable strategy for improving a protein's half-life in circulation (G6). In
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`fact, Gombolz suggested that site specific conjugation at the C-terminus was
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`a strategy to avoid the problem of inactivation of a protein (G6), the exact
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`approach utilized in the '264 patent. Significantly, Knudsen I '990 teaches
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`the exendin is still biologically active when conjugated to a lipophilic
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`substituent (KI6), giving rise to an expectation that exendin would not lose
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`activity when joined to a polymer such as albumin or PEG.
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`It is axiomatic that"[ o ]bviousness does not require absolute
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`predictability of success ... all that is required is a reasonable expectation of
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`success." In re O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988). Based on
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`the many teachings in the art of how to conjugate albumin to a peptide and
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`the success in many cases of making a biologically active peptide, including
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`of exendin-4 conjugated to a lipophilic group (KI4-KI6), we conclude that a
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`person in the art would have reasonably expected the claimed conjugate to
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`possess biological activity. The claim does not require that it possesses a
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`specific degree of activity, so even if a reduction of activity is observed, the
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`conjugate of exendin-4 and albumin would still fall within the scope of the
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`claim.
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`Secondary considerations
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`Patent Owner provided evidence of secondary considerations for an
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`exendin-albumin conjugate known as "PC-DAC™: Exendin-4." In making
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`an obviousness determination, secondary considerations must be considered
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`if present. Graham v. John Deere Co. of Kan. City, 3 83 U.S. 1, 17-18
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`(1966); TriMed Inc. v. Stryker Corp., 608 F.3d 1333, 1343 (Fed. Cir. 2010).
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`The exendin peptide PC-DAC™: Exendin-4 is linked via its C(cid:173)
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`terminal amino acid to albumin through a linker (PO Appeal Br. 15). During
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`prosecution, Patent Owner presented evidence said to show that PC-DAC™:
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`Exendin-4 "unexpectedly reduces the incidence of nausea and vomiting in
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`Type 2 diabetic patients as compared to unconjugated exedin-4." (!d.). The
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`data showing the reduction in nausea and vomiting said to be unexpected is
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`from page 17 of U.S. Patent Application No. 2007/0207958 (Application
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`Serial No. 11/595,576). We reproduce that table below:
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`”l"'.s*t}3I...l?.
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`Exentide is synthetic exendin—4 and C.IC—l l34—PC is PC—DACTM:
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`Exendin-4 (Patent Owner Remarks, dated May 5, 2009, p. 34). According to
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`Patent Owner on page 34 of those remarks:
`
`Exenatide (synthetic exendin—4) is the active ingredient
`of Byetta®.
`It is currently used at doses of 10 pg for the
`treatment of type 2 diabetes. The table above shows that 35%
`of patients receiving a single 10 pg subcutaneous dose of
`exenatide experienced nausea and 21% experienced vomiting.
`When PC-DACTM:Exendin-4 is dosed at l250 pg, patients
`experienced a glucose lowering response comparable to
`exenatide dosed at 10 pg (patients showed a mean glucose
`reduction from baseline of 15% to 25%). However, none of
`these patients experienced nausea or vomiting. Even at doses
`three times this amount (i.e., 3750 pg) the incidence of
`nausea and vomiting were still lower than incidence of nausea
`and vomiting of exenatide dosed at 10 pg. Furthermore, when
`PC-DACTM:Exendin—4 is overdosed at 5000 pg, it still exhibits
`fewer incidents of nausea and vomiting than exenatide that is
`overdosed at 100 pg. Based on these unexpected results, any
`indicia of obviousness are overcome.
`
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`The Examiner found the evidence of reduced incidence of nausea and
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`vomiting insufficient to overcome the rejection. The Examiner states:
`
`This finding is not disclosed in the patent specification, the
`property is not the subject of the instant claims and there is
`insufficient evidence to ascertain whether the property is related
`to the specific albumin conjugate or to polymer conjugates in
`general. The prior art already establishes a prima facie case for
`the claimed compounds for the reasons of extending bioactivity
`and half-life. Accordingly, the disclosure of a previously
`unrecognized property is insufficient evidence to overcome the
`instant prima facie case.
`(RAN 20.)
`
`The Examiner's failure to consider the evidence is improper.
`
`Evidence of unexpected results does not have to appear in the patent
`
`specification or to have been known at the time the patent application was
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`filed. Genetics Institute, LLC v. Novartis Vaccines and Diagnostics Inc.,
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`655 F.3d 1291, 1307 (Fed. Cir. 2011)("Although the§ 103 analysis remains
`
`properly focused 'at the time the invention was made,' it would be error to
`
`prohibit a patent applicant or patentee from presenting relevant indicia of
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`nonobviousness, whether or not this evidence was available or expressly
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`contemplated at the filing of the patent application .... Relevant secondary
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`considerations often are not manifest even until well after the issuance of a
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`patent."); Knoll Pharmaceutical Co. v. Teva Pharmaceutical USA Inc., 367
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`F.3d 1381, 1385 (Fed. Cir. 2004)("Evidence developed after the patent grant
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`is not excluded from consideration, for understanding of the full range of an
`
`invention is not always achieved at the time of filing the patent
`
`application .... There is no requirement that an invention's properties and
`
`advantages were fully known before the patent application was filed, or that
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`the patent application contains all of the work done in studying the
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`invention, in order for that work to be introduced into evidence in response
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`to litigation attack."); In re Chu, 66 F.3d 292, 299 (Fed. Cir. 1995)("We
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`have found no cases supporting the position that a patent applicant's
`
`evidence and/ or arguments traversing a § 1 03 rejection must be contained
`
`within the specification.")
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`The results clearly show that the subjects administered a therapeutic
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`dosage of 1250 J.!g ofPC-DAC™: Exendin-4 experienced no nausea or
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`vomiting, while at an equivalent therapeutic dosage of 10 Jlg of exendin-4,
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`36% experienced nausea and 21% vomiting (above). This result
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`demonstrates that the albumin linkage of the exendin-albumin conjugate is
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`responsible for the reduction in nausea and vomiting since such adverse
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`side-effects were observed with the unconjugated exedin-4 but not with the
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`conjugate. Thus, the Examiner erroneously dismissed this evidence of
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`secondary considerations in consideri