Filed: November 8, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`KVK-TECH, INC. and
`FLAT LINE CAPITAL, LLC,
`Petitioners,
`
`v.
`
`SILVERGATE PHARMACEUTICALS, INC.,
`Patent Owner.
`
`————————————————
`Case PGR2017-00039
`Patent 9,463,183
`————————————————
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`I.
`II.
`
`C.
`
`D.
`
`E.
`
`PRECISE RELIEF REQUESTED ................................................................. 1
`REASONS FOR RELIEF ............................................................................... 1
`A.
`Introduction .......................................................................................... 1
`B.
`Background .......................................................................................... 3
`QbrelisTM Is An Innovative Drug Formulation For
`1.
`Patients Suffering From Hypertension, Heart Failure,
`And Acute Myocardial Infarction .............................................. 3
`Prosecution History Of The ’183 Patent .................................... 5
`2.
`The Petition Should Be Rejected For Rule Violations ........................ 5
`1.
`Ground 3 Fails To Identify The Specific Evidence On
`Which It Relies ........................................................................... 5
`The Petition Fails To Provide A Detailed Explanation Of
`The Significance Of The References Upon Which It
`Relies .......................................................................................... 7
`Claim Construction............................................................................... 9
`1.
`“Stable” ...................................................................................... 9
`KVK Has Not Shown A Lack Of Enablement .................................. 11
`1.
`The Enablement Standard ........................................................ 11
`2.
`KVK Failed To Articulate The Proper Standard For
`Enablement ............................................................................... 12
`KVK Failed To Show Lack Of Enablement In View Of
`The Disclosed Formulations And Preparation Instructions ..... 13
`KVK Failed To Show That The Claimed Stability Profile
`Is Not Enabled .......................................................................... 16
`Submitting Post-Filed Lisinopril Measurements Is Not A
`Showing Of Non-Enablement .................................................. 19
`KVK Improperly Shifts The Enablement Burden Onto
`Silvergate ................................................................................. 20
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
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`7.
`
`2.
`
`b.
`
`c.
`
`d.
`
`F.
`
`G.
`
`H.
`
`KVK Advances Contradictory Positions For Its
`Enablement and Obviousness Arguments ............................... 21
`KVK Has Failed To Show Lack Of Written Description
`(Ground 2) .......................................................................................... 23
`1.
`The Written Description Standard ........................................... 23
`2.
`KVK Fails To Show Lack Of Written Description When
`The Claimed Formulations Are Fully Described In The
`Specification ............................................................................. 24
`The Challenged Claims Would Not Have Been Obvious Over
`Beidel, Nerurkar, Pharma Compounding Sept. 2006, and Beidel
`Two (Ground 3) .................................................................................. 30
`1.
`KVK Fails To Establish Any Motivation To Combine
`The References With A Reasonable Expectation Of
`Success ..................................................................................... 30
`a.
`KVK Fails To Show Motivation To Combine The
`References To Achieve The Claimed Formulation ....... 31
`The References Do Not Teach Or Suggest The
`Claimed Sodium Benzoate Concentration..................... 38
`KVK Presents Art that Teaches Away From The
`Selection Of Sodium Benzoate As A Preservative ....... 39
`A Lisinopril Formulation That Is Stable At About
`25°C For At Least 12 Months Would Not Be
`Predictable Based On The Cited References ................. 41
`KVK Fails To Identify A Lead Or Reference
`Composition To Be Modified In Beidel .................................. 46
`Nerurkar Is Non-Analogous Art .............................................. 47
`The Dependent Claims Are Not Obvious Over The
`References ................................................................................ 52
`KVK Relies On Impermissible Hindsight To Arrive At The
`Claimed Invention .............................................................................. 53
`III. CONCLUSION ............................................................................................. 55
`CERTIFICATE OF WORD COUNT ..................................................................... 57
`EXHIBIT LIST ....................................................................................................... 58
`
`3.
`4.
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`TABLE OF AUTHORITIES
`
`Page
`
`CASES
`Alcon Research Ltd. V. Barr Labs, Inc.,
`745 F.3d 1180 (Fed. Cir. 2014) ............................................................... 24, 25
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) ..................................................................... 25
`Ariad Pharm., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) (en banc) ......................................... 13, 23, 24
`Bell & Howell Document Mgmt. Prods. Co. v. Altek Sys.,
`132 F.3d 701 (Fed. Cir. 1997) ....................................................................... 11
`Boehringer Ingelheim Int’l GmbH v. Biogen Inc.,
`No. IPR2015-00418 (2015) ............................................................................. 7
`D'Agostino v. MasterCard Int’l Inc.,
`844 F.3d 945 (Fed. Cir. 2016) ......................................................................... 9
`Eli Lilly & Co. v. Actavis Elizabeth LLC,
`435 Fed. Appx. 917 (Fed. Cir. 2011) ............................................................ 20
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ....................................................................... 23
`In re Brana,
`51 F.3d 1560 (Fed. Cir. 1995) ....................................................................... 20
`In re Buchner,
`929 F.2d 660 (Fed. Cir. 1991) ....................................................................... 14
`In re Clay,
`966 F.2d 656 (Fed. Cir. 1992) ....................................................................... 48
`In re Klein,
`647 F.3d 1343 (Fed. Cir. 2011) ..................................................................... 48
`In re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) ....................................................................... 25
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) ..................................................................... 38
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988) ................................................................. 11, 12
`Janssen Pharmaceutica N.V. v. Teva Pharmaceuticals USA, Inc.,
`583 F.3d 1317 (Fed. Cir. 2009) ............................................................... 19, 20
`
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`KSR International Co. v. Teleflex Inc.,
`127 S.Ct. 1727 (2007) .................................................................................... 31
`Monolithic Power Sys., Inc. v. O2 Micro Int'l Ltd.,
`558 F.3d 1341 (Fed. Cir. 2009) ..................................................................... 23
`PPG Industries v. Guardian Industries Corp.,
`75 F.3d 1558 (Fed. Cir. 1996) ....................................................................... 22
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d (Fed. Cir. 2007) .............................................................................. 31
`TriVascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) ..................................................................... 10
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ..................................................................... 46
`Velander v. Garner,
`348 F.3d 1359 (Fed. Cir. 2003) ..................................................................... 36
`STATUTES
`35 U.S.C. § 103 ........................................................................................................ 48
`35 U.S.C. 282(b)(2).................................................................................................... 5
`35 U.S.C. §322(a)(3) & 326(e) ................................................................................ 23
`RULES
`37 CFR 1.76(c) ........................................................................................................... 5
`37 C.F.R. § 42.104(b)(2) ............................................................................................ 6
`37 C.F.R. § 42.22(a)(2) .............................................................................................. 7
`37 CFR §42.200(b) .................................................................................................... 9
`37 C.F.R. § 42.204(b)(5) ............................................................................................ 5
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`I.
`
`PRECISE RELIEF REQUESTED
`
`In petition PGR2017-00039 (“Petition”), Petitioners, KVK-Tech, Inc. and
`
`Flat Line Capital, LLC (collectively, “KVK”), seek Post-Grant Review of Patent
`
`Owner’s (“Silvergate”) patent directed to stable liquid lisinopril formulations (U.S.
`
`Pat. No. 9,463,183 (“the ’183 patent”) (Ex. 1001) on various grounds. Because the
`
`Petition is substantively and legally defective, Silvergate respectfully requests the
`
`Board to deny the Petition in its entirety.
`
`II.
`
`REASONS FOR RELIEF
`
`A.
`
`Introduction
`
`For its first ground, KVK failed to show that it is more likely than not that at
`
`least one of the challenged claims lacks enabling disclosure in the specification.
`
`KVK sets forth an incorrect legal standard for enablement, fails to articulate a
`
`plausible argument for non-enablement, improperly attempts to shift the burden
`
`onto Silvergate, and advances a non-enablement theory that contradicts its
`
`obviousness argument.
`
`KVK’s second ground, written description, is facially defective and may be
`
`denied for that reason alone. KVK does not separately address the patentability of
`
`any claim, much less each of the challenged claims. In addition, KVK does not
`
`address the dependent claims at all. Instead, KVK generally asserts that the
`
`claimed stability profile of the independent claims lacks description based on its
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`enablement analysis. Yet precedent has established that written description and
`
`enablement are separate requirements with separate proofs.
`
`For the third ground, KVK failed to establish that the claims would have
`
`been obvious in view of the art cited. First, KVK’s argument that a person of
`
`ordinary skill in the art (“POSA”), in attempting to develop a stable formulation of
`
`lisinopril, would select a buffer having a pKa at a pH of 4.8, is based on KVK’s
`
`assertion that lisinopril is most stable at pH 4.8 (citing to KVK’s primary reference
`
`Beidel (Ex. 1005))1. Pet. at 59. Yet Beidel does not support this assertion and
`
`1 In the Petition, KVK used an inconsistent citation format, citing to the exhibit
`
`number of each document, but referring to either the Bates page number or the
`
`original page number. Solely for the purpose of avoiding confusion and to assist
`
`the Board in accurately comparing Silvergate’s positions with regards to KVK’s
`
`reference disclosure, Silvergate herein cites to the KVK exhibits (i.e., 10XX
`
`Exhibits) using the Exhibit Name and Exhibit page number (when available), as
`
`well as the Exhibit Number and the Bates number in parentheses exemplified in the
`
`following example: Harris at 205 (Ex. 1018 at 45). However, Ex. 1001 (the ’183
`
`patent) is cited using column and line numbers. Silvergate’s exhibits (starting at
`
`2001) are presented using exhibit numbers and Bates-labeled page numbers only.
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`actually recommends buffering to pH 5.75. Ex. 1005, Conclusion. Thus, KVK’s
`
`assertion that a POSA would have had reason to select the recited buffer and pH
`
`lacks basis.
`
`Moreover, KVK has not shown motivation to combine the references with a
`
`reasonable expectation of success in achieving the claimed formulations having the
`
`recited stability profile. To the contrary, KVK relies on a reference that is non-
`
`analogous art (i.e., Nerurkar (Ex. 1009)) and cites to another reference (i.e.,
`
`Thompson (Ex. 1016)) that teaches away from the use of one of the recited
`
`elements. Finally, based on the references KVK cites, a POSA would have no
`
`expectation of success in achieving the claimed formulations having the recited
`
`stability profile because the references whether taken alone or in combination fail
`
`to teach or suggest a lisinopril formulation of any composition demonstrating the
`
`requisite stability.
`
`1.
`
`B.
`
`Background
`QbrelisTM Is An Innovative Drug Formulation For Patients
`Suffering From Hypertension, Heart Failure, And Acute
`Myocardial Infarction
`The ’183 patent belongs to a patent family with claims covering QbrelisTM,
`
`the first and only FDA-approved lisinopril oral solution. Ex. 2016 at 1. QbrelisTM
`
`is indicated for the treatment of hypertension in adults and pediatric patients 6
`
`years of age and older, as adjunct therapy for heart failure, and for treatment of
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`acute myocardial infarction in adults. Ex. 2004 at 1. The active ingredient in
`
`QbrelisTM is lisinopril, an angiotensin-converting enzyme (ACE) inhibitor that,
`
`prior to the invention of QbrelisTM, was only available as oral tablets. Ex. 1001 at
`
`1:33-53.
`
`QbrelisTM provides various advantages over oral tablets including ease of
`
`administration, dosing accuracy, accessibility to patient populations such as the
`
`elderly and children, and increased patient compliance. Id. at 2:24-29. A
`
`significant portion of the population has difficulty ingesting oral tablets, which are
`
`not recommended for children and the elderly for this reason. Id. at 2:30-38.
`
`Moreover, because lisinopril dosage is based on weight, oral tablets must be
`
`crushed and reconstituted in liquid form by a compounding pharmacist in order to
`
`obtain a dose for children. Id. at 2:47-51. This dose is often inaccurate due to
`
`variability in the compounding process such as incomplete dissolution of the
`
`crushed lisinopril powder and lisinopril instability in the reconstitution liquid. Id.
`
`at 2:51-59.
`
`QbrelisTM overcomes the deficiencies of oral tablets with a liquid
`
`formulation that allows for accurate dosing without requiring a compounding
`
`pharmacist and for improved administration in populations with swallowing
`
`difficulties. Moreover, QbrelisTM is precisely formulated to provide superior long-
`
`term lisinopril stability in solution. File History (Ex. 1003 at 185-86). The ’183
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`patent claims encompass the unique and innovative liquid lisinopril formulation
`
`embodied by QbrelisTM.
`
`2.
`
`Prosecution History Of The ’183 Patent
`
`The ’183 patent issued from U.S. Patent Application Number 14/934,752,
`
`filed on November 6, 2015, and claims priority to Provisional Application Number
`
`62/249,011 (“the ’011 application”), filed October 30, 2015. Apparently relying
`
`on an application data sheet (“ADS”) that does not explicitly include the priority
`
`claim, KVK incorrectly asserts that the ’183 patent did not claim priority to the
`
`’011 application, and therefore is not entitled to the priority date of October 30,
`
`2015. Pet. at 19-20. However, a corrected ADS containing the priority claim,
`
`which was filed on the application filing date in accordance with 37 C.F.R. 1.76(c).
`
`File History (Ex. 1003 at 79). Therefore, the ’183 patent properly claims priority
`
`to the ’011 application and is entitled to the priority date of October 30, 2015.
`
`C.
`
`The Petition Should Be Rejected For Rule Violations
`
`1.
`
`Ground 3 Fails To Identify The Specific Evidence On
`Which It Relies
`
`KVK’s Petition violates 37 C.F.R. § 42.204(b)(5), which requires that “the
`
`petition must set forth … a statement of … [t]he specific statutory grounds
`
`permitted under 35 U.S.C. 282(b)(2) or (3) on which the challenge to the claim is
`
`based … Where the grounds for unpatentability are based on prior art, the petition
`
`must specify where each element of the claim is found in the prior art … and …
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`[t]he exhibit number of the supporting evidence relied upon to support the
`
`challenge.”
`
`For Ground 3, the Petition identifies only four references, i.e., Beidel (Ex.
`
`1005), Nerurkar (Ex. 1009), Pharma Compounding Sept. 2006 (Ex. 1010) and
`
`Beidel Two (Ex. 1006). Pet. at 4. Yet, KVK introduces additional references to
`
`supply elements not taught by the four references. For example, KVK cites to
`
`Nerurkar for purportedly teaching the claimed element of sodium benzoate as a
`
`preservative, stating “Nerurkar discloses sodium benzoate in the range of 1.0-2.0
`
`mg/ml.” Pet. at 61. However, because this stated range in Nerurkar is higher than
`
`the “about 0.8 mg/mL” required by the ’183 patent claims, KVK points to yet two
`
`additional references (i.e., Ex. 1013 and Ex. 1020) for allegedly teaching additional
`
`sodium benzoate concentrations of 0.1% to 5% and specifically 0.5%. In a further
`
`example, KVK sweeps in yet more references to support KVK’s position that “a
`
`POSA would have had reason to try, and been motivated to use, xylitol in place of
`
`sorbitol as a sweetener.” Pet. at 56, citing to Ex. 1011 and Ex. 1020 (supra).
`
`The Board should reject the Petition because of this defect alone. In an
`
`analogous situation in an Inter Partes Review, the Board denied institution for
`
`failure to comply with 37 C.F.R. § 42.104(b)(2), where Petitioner “represents this
`
`challenge as based on McNeil alone, yet relies on at least eight additional
`
`references to explain why [the asserted claim] would have been obvious over
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`McNeil.”. (Citations omitted); see Boehringer Ingelheim Int’l GmbH v. Biogen
`
`Inc., No. IPR2015-00418 (2015), Paper 14 at 17 and 31.
`
`KVK’s obviousness challenge based on Beidel (Ex. 1005), Nerurkar (Ex.
`
`1009), Pharma Compounding Sept. 2006 (Ex. 1010) is admittedly insufficient
`
`because it facially relies on additional references allegedly providing elements or
`
`motivation not provided by the four cited references. Neither the Board nor
`
`Silvergate should have to speculate about the petition grounds. Ground 3 should
`
`be rejected for failure to identify its basis with specificity.
`
`2.
`
`The Petition Fails To Provide A Detailed Explanation Of
`The Significance Of The References Upon Which It Relies
`
`Second, KVK’s Petition violates 37 C.F.R. § 42.22(a)(2), which requires
`
`that “the petition must include… [a] full statement of the reasons for the relief
`
`requested, including a detailed explanation of the significance of the evidence
`
`including material facts ….”
`
`For example, KVK points to Beidel as allegedly teaching that lisinopril is
`
`most stable at a pH of 4.8 at 25°C, yet overlooks that Beidel only discloses testing
`
`of one pH at 25°C and thus, there are no other pH values at 25°C for comparison.
`
`Moreover, KVK does not address the data in Beidel where samples at multiple pH
`
`values were tested and stored at the higher temperature of 45°C, which
`
`demonstrated that the sample at pH 5.75 (rounded in the table to 5.8) had the
`
`highest amount of lisinopril remaining, indicating that sample at pH 5.75 was the
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`most stable. Indeed, the stated conclusions of Beidel recommend buffering to a pH
`
`of 5.75. Ex. 1005, Conclusion. Rather than address the data, KVK and its expert
`
`(Kibbe, a co-author of Beidel) assert that the pH of 5.75 was a “typographical error
`
`since it was not supported by the data;” however—even if true—the error would
`
`not have been known to a POSA. Pet. at 63 n.5. Moreover, Benjamin Beidel (the
`
`exhibit’s lead author) was silent on this point in his Declaration. Ex. 1021. Dr.
`
`Kibbe’s willingness to testify to an uncorroborated, secret “error” that is
`
`inconsistent with the actual data in Beidel (and about which Beidel himself
`
`remains silent) speaks volumes about Dr. Kibbe’s reliability.
`
`Further, although the claims of the ’183 patent are directed to a formulation
`
`of lisinopril, KVK cites to the Nerurkar reference, which concerns a formulation
`
`for a different, unrelated active agent (i.e., alendronic acid), yet fails to explain
`
`why a POSA would turn to such a reference in developing a lisinopril formulation.
`
`Additionally, KVK overlooks a key feature of the invention of Nerurkar (i.e.,
`
`“[t]he inclusion of a relatively large amount of buffer is a key feature in this
`
`invention”; Nerurkar at 6 (Ex. 1009 at 8). Even assuming a POSA would have
`
`considered Nerurkar, KVK fails to explain why the POSA would have selected
`
`vastly smaller amounts of buffer against Nerurkar’s “key” teaching.
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`Claim Construction
`D.
`In a Post-Grant Review, an unexpired claim is given its broadest reasonable
`
`interpretation in light of the specification. 37 C.F.R. §42.200(b). An interpretation
`
`inconsistent with the specification and the prosecution history is unreasonable.
`
`D'Agostino v. MasterCard Int’l Inc., 844 F.3d 945, 948-51 (Fed. Cir. 2016).
`
`KVK’s claim construction positions are unreasonably broad even under the
`
`“broadest reasonable interpretation” standard, leading to an improper and
`
`unrealistic assessment of obviousness. Because KVK’s constructions conflict with
`
`the specification and prosecution history, they must be rejected.
`
`1.
`
`“Stable”
`
`The ’183 patent claims recite a “stable oral liquid formulation” and “the
`
`formulation is stable at about 25±5 °C for at least 12 months.” The ’183 patent
`
`expressly defines “stable”:
`
`Stable as used herein refer to lisinopril oral liquid formulations
`having about 95% or greater of the initial lisinopril amount and
`about 5% w/w or less total impurities or related substances at
`the end of a given storage period.
`
`Ex. 1001 at 15:1-5. Silvergate referenced this definition during prosecution, and
`
`further explained that “this stability is required by the claims for at least a duration
`
`of 12 months at about 25±5 °C.” File History (Ex. 1003 at 167). The ’183 patent
`
`further provides:
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`liquid
`lisinopril oral
`the stable
`In some embodiments,
`formulations have about 5% w/w, about 4% w/w, about 3%
`w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about
`1% w/w, or about 0.5% w/w total impurities or related
`substances.
`
`Ex. 1001 at 15:8-12. Based on these teachings, a POSA would have known that in
`
`the context of this invention, stability of the claimed oral liquid formulations can
`
`be assessed with respect to the lisinopril content or the content of impurities, and
`
`that the minimum lisinopril content is 95%, and the maximum impurity content is
`
`5%.
`
`Rather than address the express definition, KVK asserts “prior to the ’183
`
`patent, it was the understanding of POSAs that a formulation of lisinopril was
`
`considered stable if the percent remaining was greater than 90%.” Pet. at 77
`
`(emphasis added).2 KVK urges an unreasonably broad definition based on asserted
`
`extrinsic knowledge, rather than looking to the plain language of the claims first
`
`and intrinsic evidence as needed. TriVascular, Inc. v. Samuels, 812 F.3d 1056,
`
`1062 (Fed. Cir. 2016) (“words of the claim must be given their plain meaning,
`
`2 In this paper, all emphases are added unless otherwise indicated.
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`unless such meaning is inconsistent with the specification and prosecution
`
`history.”). Using extrinsic evidence to interpret claims is proper only when the
`
`claim language remains genuinely ambiguous after consideration of the intrinsic
`
`evidence. Bell & Howell Document Mgmt. Prods. Co. v. Altek Sys., 132 F.3d 701,
`
`705-06 (Fed. Cir. 1997).
`
`E.
`
`KVK Has Not Shown A Lack Of Enablement
`
`KVK has failed to show that it is more likely than not that at least one of the
`
`claims challenged in the Petition is unpatentable for failure to meet the enablement
`
`requirement. KVK advances an incorrect legal standard for enablement, fails to
`
`articulate a plausible argument for non-enablement, improperly attempts to shift
`
`the burden onto Silvergate, and advances a non-enablement theory that contradicts
`
`its obviousness argument.
`
`1.
`
`The Enablement Standard
`
`The standard for enablement is whether the experimentation needed to
`
`practice the invention is undue or unreasonable. In re Wands, 858 F.2d 731, 737
`
`(Fed. Cir. 1988). Under this standard, enablement is satisfied when the disclosure
`
`at the time of filing contained sufficient information regarding the subject matter of
`
`the claims to enable one skilled in the pertinent art to make and use the claimed
`
`invention without undue experimentation. Id. Various factors may be considered
`
`in assessing whether experimentation is “undue” and can include the breadth of the
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`claims, the nature of the invention, the state of the prior art, the level of one of
`
`ordinary skill, the level of predictability in the art, the amount of direction provided
`
`by the inventor, the existence of working examples, and the quantity of
`
`experimentation needed to make or use the invention based on the content of the
`
`disclosure. Id.
`
`2.
`
`KVK Failed To Articulate The Proper Standard For
`Enablement
`
`KVK argues that the claims of the ’183 patent are not enabled because the
`
`specification supposedly does not disclose working examples of liquid lisinopril
`
`formulations that satisfy all of the claim elements, including the claimed stability
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`profile. Pet. at 29. This argument fails because it does not meet KVK’s burden of
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`showing that undue experimentation is required for a POSA to make and use the
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`claimed invention.
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`Indeed, KVK does not even attempt to advance an undue experimentation
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`hypothesis, instead conflating enablement and written description to allege that
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`“the claims are not enabled because the specification does not show that the
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`inventors were in possession of a lisinopril formulation with the claimed stability
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`profile.” Id.
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`Showing possession of the claimed invention is part of the written
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`description analysis and not the proper standard for determining enablement.
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`Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en
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`banc) (explaining written description and holding it to be separate and distinct
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`from enablement). Moreover, KVK provides no authority for its assumption that
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`every claimed composition and property limitation must be expressly disclosed and
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`confirmed in a single working example within the specification in order to enable a
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`claim. Pet. at 29. Accordingly, KVK failed to show non-enablement of the ’183
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`claims at least because it relies upon an improper legal standard for enablement.
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`3.
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`KVK Failed To Show Lack Of Enablement In View Of The
`Disclosed Formulations And Preparation Instructions
`
`In addition to applying an erroneous standard for enablement, KVK also
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`failed to articulate why the ’183 patent claimed formulations are supposedly not
`
`enabled when the exact components of the claimed formulations and their amounts
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`are explicitly provided in the specification along with instructions for their
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`manufacture.
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`For instance, Example F discloses formulations prepared according to Table
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`F-1, including all the claimed components at the claimed concentrations and
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`properties corresponding to the patented claims. Ex. 1001 at Table F-1.
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`Formulation F7 recites all the components and concentrations of independent
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`claims 1 and 12, whereas formulation F1 lists all the components that give rise to
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`the claimed percentages (w/w of solids) as well as concentrations of independent
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`claim 6.3 Id. Moreover, F1 and F7 have the same citrate buffer concentration
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`because the citric acid of F1 forms “~1.44 mg/mL sodium citrate in situ” when it is
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`dissolved in solution. File History (Ex. 1003 at 183). As such, F1 and F7 are
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`compositionally equivalent aside from a slight difference in pH. Thus, F1 provides
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`support for each independent claim of the ’183 patent.
`
`KVK claims that there is no support in the specification for formulation F1
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`containing 1.44 mg/mL of sodium citrate anhydrous formed in situ because F1
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`only recites citric acid anhydrous. Pet. at 29-30. However, a POSA would have
`
`known that citric acid deprotonates to form citrate in water at pH 5 based on its
`
`known pKa values, which are basic chemistry principles not required to be in the
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`specification to establish enablement. Harris at 182 (Ex. 1018 at 22). A patent
`
`need not teach, and preferably omits, what is well known in the art. In re Buchner,
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`929 F.2d 660, 661 (Fed. Cir. 1991). Moreover, KVK takes a contradictory position
`
`in its obviousness argument by asserting that Nerurkar’s disclosure of a citric acid
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`buffer adjustable by NaOH reads on the claimed 1.44 mg/mL sodium citrate
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`because it “is consistent with Applicants’ statement during prosecution that sodium
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`3 The specification also discloses the exact language of independent claim 6.
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`Ex. 1001 at 2:52-60.
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`citrate forms in situ at the approximately claimed amount based on addition of
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`NaOH.” Pet. at 57-58. Thus, KVK acknowledges the art knew that an acid (citric
`
`acid) can deprotonate in aqueous solution to form the conjugate base (citrate).
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`Furthermore, Example F provides instructions for preparing the finished
`
`formulations of Table F-1 whereby the “components were dissolved in about 80%
`
`of the final volume of water then additional water was added to bring the solution
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`to final volume.” Ex. 1001 at 34:45-47. Subsequently, the “pH was adjusted to the
`
`target pH with hydrochloric acid or sodium hydroxide,” which corresponds to the
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`pH adjustment limitation in independent claim 12. Id. at 34:47-48. Such steps can
`
`be performed by a POSA, especially because these steps are plainly described in
`
`the ’183 patent. Moreover, solubility of the ingredients is not a problem because
`
`the ingredients readily dissolve in water at concentrations higher than in the
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`claimed formulations.4 Meanwhile, KVK provides no evidence challenging the
`
`disclosed methodology for preparing the claimed formulations.
`
`4 Lisinopril has a solubility of 97 mg/ml. Ex. 2011, Lisinopril. Xylitol has a
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`solubility of 64.2 mg/ml. Ex. 2015, Xylitol. Citric acid has a solubility of 59.2
`
`w/w at 20oC. Ex. 2013, Citric Acid. Sodium benzoate has a solubility of 1g/1.8ml.
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`Ex. 2014, Sodium Benzoate.
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`4.
`
`KVK Failed To Show That The Claimed Stability Profile Is
`Not Enabled
`
`A core argument of KVK’s purported lack of enablement is that the novel
`
`aspect of the ’183 claims, i.e., the lisinopril stability profile, is not enabled due to
`
`Example F not directly measuring lisinopril content. Pet. at 29-30. KVK argues
`
`that because Example F did not measure the initial lisinopril amount and only
`
`tested for the diketopiperazine and hydrolysate degradants of lisinopril rather than
`
`the actual amount of lisinopril remaining at the end of a given storage period, an
`
`inaccurate measurement was produced that failed to account for other possible
`
`degradants. Id. at 30. KVK concludes that the limitation “wherein the formulation
`
`is stable at about 25±5°C. for at least 12 months” of independent claims 1, 6, and
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`12 is not enabled because the inventors failed to show they “were in possession of
`
`a lisinopril formulation with the claimed stability profile.” Pet. at 29. KVK further
`
`alleges that dependent claims 4, 5, 10, and 11 lack data for the claimed stability
`
`profile of 18 or 24 months. Id. at 40.
`
`As established supra, enablement requires that the disclosure enable a POSA
`
`to pra