IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`) ) ) I
`
`OSI PHARMACEUTICALS, |NC.,
`
`PFIZER, INC., and GENENTECH INC.,
`
`Plaintiffs,
`
`v.
`
`) Civ. No. O9—185—SLR
`
`) ) )
`
`)
`
`MYLAN PHARMACEUTICALS |NC.,
`
`Defendant.
`
`Jack B. Blumenfeld, Esquire and Maryellen Noreika, Esquire of Morris, Nichols, Arsht &
`Tunnell LLP. Counsel for Plaintiffs. Of Counsel: Leora Ben-Ami, Esquire, Benjamin
`Hsing, Esquire, Daniel Bogliogi, Esquire and Sapna W. Palla, Esquire of Kaye Scholer
`LLP.
`
`John C. Phillips, Jr., Esquire and Megan Haney, Esquire of Phillips, Goldman & Spence,
`P.A. Counsel for Defendant. Of Counsel: James H. Wallace, Jr., Esquire, Mark A.
`Pacella, Esquire, Matthew J. Dowd, Esquire and Adrienne Johnson, Esquire of Wiley
`Rein LLP.
`
`OPINION
`
`Dated: May 1, 2012
`Wilmington, Delaware
`
`APOTEX EX. 1028-001
`
`

`
` N ge
`
`I.
`
`INTRODUCTION
`
`This action arises out of the filing of Abbreviated New Drug Applications
`
`(“ANDAs") by Mylan Pharmaceuticals inc. (“My|an") and Teva Pharmaceuticals USA,
`
`lnc. (“Teva") seeking to market generic versions of Tarceva® (erlotinib tablets), used to
`
`treat certain indications of non-small cell lung cancer and pancreatic cancer.
`
`Plaintiff OSI Pharmaceuticals, Inc. (“OSl") is the holder of approved New Drug
`
`Application (“NDA”) No. 021743 for Tarceva®. OSI and plaintiff Pfizer, Inc. (“Pfizer") are
`
`owners of U.S. Patent Nos. 5,747,498 (“the ‘498 patent”), 6,900,221 (“the ‘221 patent")
`
`and 7,087,613 (“the ‘613 patent”). Plaintiff Genentech Inc. (“Genentech") is a “co-
`
`exclusive licensee” of these patents, which are listed in the Food and Drug
`
`Administration's (“FDA's”) publication titled “Approved Drug Products with Therapeutic
`
`Equivalence Evaluations” (known as the “Orange Book”)‘ for Tarceva®.
`
`(D.l. 54 at ‘[11]
`
`14, 19, 21) in December 2009, the ‘498 patent was reissued as U.S. Reissue Patent
`
`No. RE 41,065 (“the RE ‘065 patent"), which has been added to the Orange Book for
`
`Tarceva®.
`
`in February 2009, OSI and Pfizer received a letter from Teva notifying them that
`
`Teva had filed ANDA No. 91-059 with a Paragraph IV certificationz alleging that the
`
`‘498, ‘221 and ‘613 patents are invalid, unenforceable, and/or not infringed by Teva’s
`
`generic erlotinib hydrochloride tablets.
`
`(Id. at 1] 26) Shortly thereafter, also in February
`
`2009, Mylan sent notice to OSI and Genentech that Mylan filed ANDA No. 91-002 with a
`
`‘The Orange Book must list “each drug which has been approved for safety and
`effectiveness through an NDA." See 21 U.S.C. §§ 355(j)(A)(ii).
`
`2See 21 u.s.c. § 355(j)(2)(A)(vii)(lV).
`
`APOTEX EX. 1028-002
`
`

`
`Paragraph IV certification alleging that the ‘498, ‘221 and ‘613 patents are invalid,
`
`unenforceable, and/or not infringed by Mylan’s generic erlotinib hydrochloride tablets.
`
`(Id. at 1] 31) On March 19, 2009, plaintiffs filed Civ. Nos. 09-185 and 09-186, alleging
`
`infringement of the ‘498, ‘221 and ‘613 patents by Teva and Mylan, respectively.3 The
`
`cases were consolidated.
`
`In January 2010, after the issuance of the RE ‘065 patent,
`
`plaintiffs filed an amended and supplemental consolidated complaint in Civ. No. 09-185,
`
`alleging infringement of the RE ‘065, 221 and ‘613 patents by Teva and Mylan.
`
`(Id.)
`
`Teva and Mylan brought counterclaims for noninfringement and for invalidity.
`
`(D.|. 56,
`
`57)
`
`After the close of fact discovery, Teva moved to amend its pleadings to add the
`
`defenses of invalidity based on obviousness-type double-patenting; the court denied the
`
`motion.
`
`(D.|. 172, 213) A pretrial conference was held March 3, 2011. Teva and Mylan
`
`conceded infringement of claims 1, 2, 4, 8, 34 and 35 of the RE ‘065 patent and claim
`
`53 of the ‘221 patent.
`
`(D.|. 198 at 2) On March 11, 2011, the court denied Teva’s
`
`motion for reconsideration of the court’s denial of its motion to amend.
`
`(D.l. 218) A
`
`settlement was reached between plaintiffs and Teva on the eve of trial.
`
`(D.|. 222, 223)
`
`Mylan presented its invalidity defenses during a five-day bench trial commencing March
`
`14, 2011. On June 30, 2011, the court entered an order enjoining Mylan from launching
`
`its generic product until the court’s decision issued.
`
`(D.|. 231) The validity issues have
`
`been fully briefed post-trial.
`
`(D.|. 232, 233, 234) The parties represent that the 30-
`
`3898 35 U.S.C. § 271(e)(2)(A) (“(2) It shall be an act of infringement to submit —
`(A) an application under section 505(j) of the Federal Food, Drug, and Cosmetic Act or
`described in section 505(b)(2) of such Act for a drug claimed in a patent or the use of
`which is claimed in a patent[.]”).
`
`APOTEX EX. 1028-003
`
`

`
`month statutory stay expires “on or about May 18, 2012.”4 (D.|. 232 at 1; D.|. 233 at 3)
`
`The court has jurisdiction pursuant to 28 U.S.C. §§ 1331, 1338(a) and 1400(b).
`
`Having considered the documentary evidence and testimony, the court makes the
`
`following findings of fact and conclusions of law pursuant to Fed. R. Civ. P. 52(a).
`
`ll. FINDINGS OF FACT AND CONCLUSIONS OF LAW
`
`A. The Technology at Issue
`
`1. EGFR and NSCLC
`
`1. A discussion of the technology at issue is best framed by an overview of
`
`epidermal growth factor receptor (“EGFR”) and its role vis-a-vis cancer cells. EGFR is a
`
`receptor tyrosine kinase that is involved in transmitting signals from the outside of a cell
`
`to the inside of a cell.
`
`In normal cells, epidermal growth factor (or “EGF”) binds to
`
`EGFR, which will cause a second EGFR or one of its family members together to bind
`
`to it, resulting in the transfer of a phosphate to the EGFR. This phosphorylation
`
`“initiates a cascade of signalling events within the cell, leading to increased survival and
`
`increased cell proliferation[.]” (D.|. 226 at 466:14-467:2) A EGFR tyrosine kinase
`
`inhibitor is a small molecule that penetrates a cell, binds to the catalytic portion of the
`
`kinase, and inhibits its enzymatic activity in transferring a phosphate.
`
`(Id. at 46725-8)
`
`There are also EGFR kinase inhibitors that are not tyrosine kinase inhibitors, such as
`
`monoclonal antibodies that bind to EGFR, that are not the subject of the patents in suit.
`
`(Id. at 467218-23)
`
`2. Receptor tyrosine kineases are “frequently aberrantly expressed in common
`
`4See 21 u.s.c. § 355(j)(5)(B)(iii).
`
`APOTEX EX. 1028-004
`
`

`
`human cancers,” and “[i]t has also been shown that epidermal growth factor receptor
`
`(EGFR) which possesses tyrosine kinase activity is mutated and/or overexpressed in
`
`many human cancers[.]” (RE ‘065, col. 1:24-48)
`
`3. There are two general types of lung cancer: non—small cell lung cancer
`
`(“NSCLC”), making up 80-85% of cases, and small-cell lung cancer (“SCLC”), which is
`
`about 10-15% of all lung cancers.
`
`(D.l. 227 at 806:18—24 (85%/15% ratio); DTX-365 at
`
`365 (80% of lung cancers classified as NSCLC, and 10% have both small—ce|l and non-
`
`small cell elements)) NSCLC is further divided into three types: adenocarcinoma,
`
`squamous cell carcinoma, and large cell carcinoma.
`
`(D.l. 224 at 70:17-24) Doctors’
`
`classification of the cancer is important because NSCLC and SCLC have “distinct
`
`morphology, genetics, biology and clinical behavior.” (DTX-433 at 310)
`
`2. Erlotinib
`
`4. Erlotinib, or N—(3—ethynylphenyl)—6,7—bis(2—methoxyethoxy)quinazolin-4—amine
`
`(formula C22H23N3O4), is a kinase inhibitor.5 The structure of erlotinib is below,
`
`highlighted to differentiate the molecu|e’s functional segments:
`
`the quinalone core
`
`(yellow); an anilino group comprised of the amine linker (purple); an analine ring
`
`(orange); 3'-position substitution with an ethynyl substituent (red); and substitution at the
`
`6,7-potisions with dimethoxyethoxy tails (green).
`
`5See gen. PubChem, erlotinib - Compound summary, available at
`http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=176870&|oc=ec_rcs.
`
`4
`
`APOTEX EX. 1028-005
`
`

`
`
`
`:2’;-.m»,;a2:ré€:9ss C‘-om
`
`(D.|. 233 at 4-5) Tarceva® contains erlotinib as the hydrochloride salt.
`
`3.
`
`‘498 and RE ‘065 patents
`
`5. The ‘498 patent was filed May 28, 1996 and issued May 5, 1998; it claims
`
`priority (as a continuation-in-part) to a PCT application filed June 6, 1995. The RE ‘065
`
`patent was issued on December 29, 2009, from a reissue patent application filed
`
`February 27, 2008. The patents, entitled “Alkynl and Azido—substituted 4-
`
`Anilinoquinazolines,” list Rodney Caughren Schnur and Lee Daniel Arnold as inventors,
`
`and are assigned to OSI and Pfizer. As a reissue patent, the RE ‘065 patent has an
`
`identical specification to the ‘498 patent.
`
`6. The disclosed invention relates to compounds ofthe formula I -
`
`and to pharmaceutically acceptable salts thereof, which compounds are useful for
`
`5
`
`APOTEX EX. 1028-006
`
`

`
`treating hyperproliferative diseases, such as cancer. The “R” groups and “n” and “m”
`
`values are defined in the specification. The invention also relates to processes of
`
`making the compounds of formula I and to methods of using them in the treatment of
`
`disease.
`
`(RE ‘065 patent, abstract) The specification recites many preferred
`
`compounds according to the invention by chemical nomenclature, which for brevity’s
`
`sake, will not be reiterated here. Erlotinib is identified as one of the specifically-
`
`preferred compounds.
`
`(ld., col. 4:15-16)
`
`7. As background, the patents provide that 4-(substituted phenylamino)
`
`quinazoline derivatives are useful in the treatment of cancers in mammals.
`
`(RE ‘065
`
`patent, col. 1:13-15) More specifically,
`
`it has been recognized that inhibitors of receptor tyrosine kinases are useful
`as selective inhibitors of the growth of mammalian cancer cells.
`For
`example, erbstatin, a tyrosine kinase inhibitor[,] selectively attenuates the
`growth in athymic nude mice of transplanted human mammary carcinoma
`which expresses epidermal growth factor tyrosine kinase (EGFR) but is
`without effect on the growth of another carcinoma which does not express
`the EGF receptor.
`
`(Id., col. 1:49-57) The compounds of the invention are the result of the continued
`
`search for improved anti-cancer pharmaceuticals.
`
`(Id., col. 2:1-4)
`
`8. While more specific methods are also disclosed, the specification generally
`
`provides that the formula I compounds and pharmaceutically acceptable salts thereof
`
`can be prepared “by any process known to be applicable to the preparation of
`
`chemically-related compounds,” and “may be made from the appropriately substituted
`
`quinazoline using the appropriately substituted amine.” (Id., col. 8:50-56) Similarly,
`
`while specific administrative methods are discussed, the “[a]dministration of the active
`
`compounds [generally] can be effected by any method which enables delivery of the
`
`6
`
`APOTEX EX. 1028-007
`
`

`
`compounds to the site of action (e.g., cancer cells),” which methods include “oral routes,
`
`intraduedenal routes, parenteral injection .
`
`.
`
`., topical administration” and others.
`
`(Id.,
`
`col. 15:39-45)
`
`9.
`
`It is disclosed that the active compounds of the invention are potent inhibitors
`
`of EGFR and may be used on a “variety of human tumors (renal, liver, kidney, bladder,
`
`breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic
`
`carcinomas, sarcomas, glioblastomas, various head and neck tumors),” as well as for
`
`possible activity against “a range of leukemias and lymphoid malignancies” and
`
`“inflammatory, angiogenic and immunologic disorders.” (Id., col. 13:60-co|.14:23) A
`
`procedure for determining the “in vitro activity of the active compounds in inhibiting the
`
`receptor tyrosine kinase (and subsequent proliferative response, e.g., cancer)” is
`
`provided.
`
`(Id., col. 14:23-26 et seq.) The inventors state that, “[a]|though the inhibitory
`
`properties of the compounds of [t]ormula I vary with structural change as expected, the
`
`activity generally exhibited by these agents, determined in the manner described above,
`
`is in the range of |C5O = 0.001-30 pM.” (Id., col. 14:66-col. 15:2) This |C506 value is the
`
`only information that the inventors provide as to the properties of the disclosed
`
`compounds; no in vivo, pharmacokinetic or pharmacodynamic data is described.
`
`(D.l.
`
`225 at 286119-287:2; D.|. 226, 546:8-14)
`
`10. Claim 1 was consistent from the ‘498 to the RE ‘O65 patent, claiming a
`
`compound of formula I, further defining m, R‘, R2 and n. Claim 8 of the ‘498 patent was
`
`originally a Markush-style claim, listing specific permeations of the compound of claim 1.
`
`‘Generally, |C5O (or the half maximal inhibitory concentration) is a measure of the
`effectiveness of a compound in inhibiting a biochemical action.
`
`7
`
`APOTEX EX. 1028-008
`
`

`
`As reissued, claim 8 in the RE ‘065 patent now claims only erlotinib. The ‘498 patent
`
`contained claims specifically directed to the use of the compound of formula I in the
`
`treatment of cancer. As reissued, the RE ‘065 patent contains claims directed to the
`
`treatment of psoriasis.
`
`11.
`
`In summary, plaintiffs have alleged, and Mylan has stipulated to,
`
`infringement of claims 1, 2, 4, 8, 34, and 35 of the RE ‘065 patent. Claims 1, 2, and 4
`
`generically cover erlotinib, and claim 8 is specific for the compound erlotinib. Claims 34
`
`and 35 further specify that erlotinib is in the form of, respectively, a pharmaceutically
`
`acceptable salt or a hydrochloride salt.
`
`4.
`
`‘221 patent
`
`12. The ‘221 patent, entitled “Stable Polymorph on N-(3-ethyny|pheny|)-6,7-
`
`bis(2methoXyethoXy)-4-quinazolinamine hydrochloride, Methods of Production, and
`
`Pharmaceutical Uses Thereof,” was filed on November 9, 2000 and issued May 31,
`
`2005. Priority is claimed to a provisional application filed November 11, 1999. There
`
`are nine listed inventors: Timothy Norris; Jeffrey W. Raggon; Richard D. Connell,
`
`James D. Moyer; Michael J. Morin; Barbara A. Foster; Karen J. Ferrante; and Sandra L.
`
`Silberman. The assignee is OSI.
`
`13. The ‘221 patent relates to a stable form of erlotinib hydrochloride
`
`“designated the B polymorph, its production in essentially pure form, and its use,” as
`
`well as pharmaceutical compositions containing the stable polymorph B form, and to
`
`methods of treating hyperproliferative disorders (such as cancer) by administering the
`
`compound.
`
`(‘221 patent, abstract) The specification of the ‘221 patent incorporates the
`
`‘498 patent in its entirety for its disclosure of erlotinib hydrochloride as an inhibitor of
`
`8
`
`APOTEX EX. 1028-009
`
`

`
`EGFR. Also incorporated in its entirety is PCT International Publication No. WO
`
`99/55683 for its disclosure of the mesylate form of erlotinib hydrochloride.
`
`(ld., col.
`
`1:27-62) The novel polymorphs of the ‘221 patent are described as having X-ray power
`
`diffraction patterns having particular characteristic peaks.
`
`(Id., col. 2:27—col.3:3; fig. 3)
`
`14. Plaintiffs have asserted, and Mylan has stipulated to, infringement of claim
`
`53 of the ‘221 patent. Claim 53 depends from claim 44, which claims as follows:
`
`44. A method for the treatment of NSCLC (non—small cell lung cancer),
`pediatric malignancies, cervical and other tumors caused or promoted by
`human papilloma virus
`(HFV), Barrett’s esophagus
`(pre-malignant
`syndrome), or neoplastic cutaneous diseases in a mammal comprising
`administering to said mammal a therapeutically effective amount of
`pharmaceutical
`composition
`comprised
`of
`at
`least one
`of N-(3-
`ethynylphenyl)—6,7—bis(2—methoxyethoxy)—4—quinazolinamine,
`or
`pharmaceutically acceptable salts thereofin anhydrous or hydrate forms, and
`a carrier.
`
`Claim 53 depends from claim 44 and requires that the method be for the treatment of
`
`NSCLC. The specification provides that,
`
`[i]n the method, the therapeutically effective amount may be from about
`0.001 to about 100 mg/kg/day, or from about 25 to about 200 mg/day.
`In the
`method, the therapeutically effective amount may also be from about 1 to
`about 7000 mg/day; from about 5 to about 2500 mg/day; or from about 25 to
`about 200 mg/day.
`
`(ld., col. 4:31-37)
`
`B. The RE ‘065 Patent: Obviousness
`
`Insofar as the parties did not present any claim construction disputes requiring
`
`resolution (D.|. 189), the court proceeds to evaluate My|an’s first argument for invalidity:
`
`that claims 1, 2, 4, 8, 34, and 35 of the RE ‘065 patent are invalid as obvious in view of
`
`the prior art.
`
`1. Obviousness standards
`
`APOTEX EX. 1028-010
`
`

`
`15. “A patent may not be obtained .
`
`.
`
`. if the differences between the subject
`
`matter sought to be patented and the prior art are such that the subject matter as a
`
`whole would have been obvious at the time the invention was made to a person having
`
`ordinary skill in the art.” 35 U.S.C. § 103(a). Obviousness is a question of law, which
`
`depends on underlying factual inquiries.
`
`Under § 103, the scope and content of the prior art are to be determined;
`differences between the prior art and the claims at issue are to be ascertained;
`and the level of ordinary skill in the pertinent art resolved. Against this
`background the obviousness or nonobviousness of the subject matter is
`determined. Such secondary considerations as commercial success, long felt
`but unsolved needs, failure of others, etc., might be utilized to give light to the
`circumstances surrounding the origin of the subject matter sought to be
`patented.
`
`KSR Int’I Co. V. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting Graham v. John Deere
`
`C0,, 383 U.S. 1, 17-18 (1966)).
`
`16. “[A] patent composed of several elements is not proved obvious merely by
`
`demonstrating that each of its elements was, independently, known in the prior art.”
`
`KSR, 550 U.S. at 418. Likewise, a defendant asserting obviousness in view of a
`
`combination of references has the burden to show that a person of ordinary skill in the
`
`relevant field had a reason to combine the elements in the manner claimed.
`
`Id. at 418-
`
`19. The Supreme Court has emphasized the need for courts to value “common sense”
`
`over “rigid preventative rules’’ in determining whether a motivation to combine existed.
`
`Id. at 419-20. “[A]ny need or problem known in the field of endeavor at the time of
`
`invention and addressed by the patent can provide a reason for combining the elements
`
`in the manner claimed.” Id. at 420.
`
`In addition to showing that a person of ordinary skill
`
`in the art would have had reason to attempt to make the composition or device, or carry
`
`10
`
`APOTEX EX. 1028-011
`
`

`
`out the claimed process, a defendant must also demonstrate that “such a person would
`
`have had a reasonable expectation of success in doing so.” Pharmastem Therapeutics,
`
`Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed. Cir. 2007).
`
`17. A combination of prior art elements may have been “obvious to try” where
`
`there existed “a design need or market pressure to solve a problem and there [were] a
`
`finite number of identified, predictable solutions” to it, and the pursuit of the “known
`
`options within [a person of ordinary skill in the art’s] technical grasp” leads to the
`
`anticipated success.
`
`Id. at 421.
`
`In this circumstance, “the fact that a combination was
`
`obvious to try might show that it was obvious under § 103.” Id. Federal Circuit
`
`precedent has also established that “[s]tructural relationships may provide the requisite
`
`motivation or suggestion to modify known compounds to obtain new compounds,” and
`
`that particular types of structural similarity can give rise to a case of prima facie
`
`obviousness. Genetics Institute, LLC V. Novartis Vaccines and Diagnostics, Inc., 655
`
`F.3d 1291, 1312 (Fed. Cir. 2011) (citing In re Deuel, 51 F.3d 1552, 1558 (Fed. Cir.
`
`1995».
`
`18. A court is required to consider secondary considerations, or objective indicia
`
`of nonobviousness, before reaching an obviousness determination, as a “check against
`
`hindsight bias.” See In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`
`Patent Litig., ——— F.3d —-—, 2012 WL 1320225 (Fed. Cir. Apr. 16, 2012). “Such secondary
`
`considerations as commercial success, long felt but unsolved needs, failure of others,
`
`etc., might be utilized to give light to the circumstances surrounding the origin of the
`
`subject matter sought to be patented.” Graham v. John Deere Co. of Kansas City, 383
`
`U.S. 1, 17-18 (1966).
`
`11
`
`APOTEX EX. 1028-012
`
`

`
`19. “Because patents are presumed to be valid, see 35 U.S.C. § 282, an alleged
`
`infringer seeking to invalidate a patent on obviousness grounds must establish its
`
`obviousness by facts supported by clear and convincing evidence.” Kao Corp. v.
`
`Unilever U.S., lnc., 441 F.3d 963, 968 (Fed. Cir. 2006) (citation omitted).
`
`In conjunction
`
`with this burden, the Federal Circuit has explained that,
`
`[w]hen no prior art other than that which was considered by the PTO examiner is
`relied on by the attacker, he has the added burden of overcoming the deference
`that is due to a qualified government agency presumed to have properly done its
`job, which includes one or more examiners who are assumed to have some
`expertise in interpreting the references and to be familiar from their work with the
`level of skill in the art and whose duty it is to issue only valid patents.
`
`PowerOasis, Inc. V. T-Mobile USA, Inc., 522 F.3d 1299, 1304 (Fed. Cir. 2008) (quoting
`
`Am. Hoist & Derrick Co. V. Sowa & Sons, 725 F.2d 1350, 1359 (Fed. Cir. 1984)).
`
`2. My|an’s evidence
`
`a. Overview
`
`20. Mylan has identified a prior art compound differing from erlotinib only in that
`
`it contains an ethynyl group, rather than erlotinib’s methyl group, at the 3'-position. The
`
`disclosure of this compound is at example 51 of Zeneca’s European Patent Application
`
`No. 0 566 226 A1, naming Andrew John Barker as inventor, filed January 15, 1993
`
`(hereinafter, the “Barker ‘226 application”).
`
`(DTX-286) The Barker ‘226 application
`
`related to “quinazoline derivatives, or pharmaceutically acceptable salts thereof, which
`
`possess anti—cancer activity,” as well as their methods of manufacture, pharmaceutical
`
`compositions containing them, and the compounds’ use in mammals.
`
`(id. at p.2:1-5)
`
`The inventor stated that “it has been indicated [in the literature] that receptor tyrosine
`
`kinease inhibitors will prove to be useful in the treatment of a variety of human cancers”
`
`12
`
`APOTEX EX. 1028-013
`
`

`
`and, while “[m]any quinazoline detivatives are already known,” it has now been
`
`discovered that certain quinazoline derivatives possess anti-cancer properties.
`
`(Id. at
`
`p.2:32-49) The invention provides a quinazoline derivative of the formula —
`
`
`
`providing specific alternatives for the values m, n, R‘ and R2.
`
`(Id. at p.1, 59 (claim 1))
`
`21. Among the invention’s non-limiting examples, the following disclosure was
`
`provided for example 51.
`
`Example 51
`
`2~Bmmoe’chyl methyl ether {i}.83~¢l; Q} was added to a stirred mixture at B,T~ditrydrdxy-4-£3‘-mathyianili—
`m:}quinaz.o1ine {£1,534 Q), potassium carbdnate {M328 Q] and DMA (13 mi). The mixture was stirred at mibient
`temperature mas house. The mixture was evaporated and the residue was partitioned between ethyl acetate
`and water. Tha organic layer was dried (M9804) and evaporated. The residue was purified by column chro-
`rnabography using increaisingly polar mixtures of rnethyiene chloride and methanol as emem. The gum so ob-
`tained was dissolved in ethyl amtate {:1 ml} and acidified by the addition of 3 satutasad solution and hydrogen
`chlurida in dlethyl sthar. “fhe precipitate: was isalaied. There was was obtained E,7—dE~(2-mathoxye’m::xy}«d~
`{3’~i‘n9thyladilinolqizirsazciine hydrochloride (€3,293 3:), mp. 218~22[)°C.
`NMR Spectrum; (CEQSOC E13} 2.34 is. 3H3, 3.33 {x»., 81-1), 3.75~3.8 {m, 41%}. 4.14.5 (m, 45%), ‘M4 (d, 1H), 7.3?
`{t,— 11%’). 7.40 (5. 1H), MA! (rm ZH}, 83$ (3, W}, 8391 (5, 1H};
`Elemental Analysis: Found C, 59.3; H, GL4; N, 9.9;
`Cg1HfiN3o4.
`Taqmfefi C.
`H.
`N.
`
`(DTX—286 at 46) There is only one difference between this compound (6,7—di-(2-
`
`methoxyethoxy)-4-(3'-methylani|ino)quinazoline) and erlotinib: erlotinib bas an ethynyl
`
`group (HC2C—) at the 3' position of the molecule, while the compound of example 51
`
`has a methyl group (H3C—) at the 3' position, as highlighted below.
`
`13
`
`APOTEX EX. 1028-014
`
`

`
`Eriotinib
`
`Ermrzple 51 9fZem?m (B(:.¥°imr} ‘236’Applicr1.tior1
`
`
`
`(D.|. 232 at 12)
`
`22. Mylan argues that, “given a medicinal chemist’s knowledge of the chemical
`
`similarities between methyl and ethynyl, and the specific suggestion in the [prior art] to
`
`use a ‘small, non-polar group’ at that position, clear and convincing evidence
`
`establishes that it would have been obvious for a medicinal chemist, working on new
`
`EGFR inhibitors, to start with the compounds of [the Barker] ‘226 application and make
`
`er|otinib.” (D.|. 232 at 30) More specifically, it is My|an’s contention that the ordinary
`
`medicinal chemist would have:
`
`(1) started with the Barker ‘226 application; (2) identified
`
`the gap in the claim coverage as not covering alkynyl (such as ethynyl) and alkenyl; (3)
`
`recognized a suggestion in the prior art to use a small, non—po|ar group, such as
`
`ethynyl, at the 3'-position; and (4) filled the gap by putting an ethynyl group at the 3'-
`
`position of the best compounds of the Barker ‘226 application. “This approach would
`
`have satisfied the medicinal chemist’s motivation to make EGFR inhibitors other than
`
`those expressly claimed in [the Barker] ‘226 application.” (Id. at 32)
`
`b. Selection of example 51 as a starting compound
`
`23. As noted above, the earliest priority date for the RE ‘065 patent is June 6,
`
`1995. Mylan argues that, at the time of the invention, the 4-anilinoquinazolines (or “4-
`
`14
`
`APOTEX EX. 1028-015
`
`

`
`AQs”) of the Barker ‘226 application were the best starting point for making an EGFR
`
`inhibitor.
`
`(D.l. 232 at 32) My|an’s expert, Dr. Clayton Heathcock (“Heathcock”),
`
`Emeritus Professor of Chemistry from the University of California at Berkeley, testified
`
`regarding several review articles following the publication of the Barker ‘226 application
`
`(in 1993) indicating that quinazolines were ideal in this regard.
`
`(D.l. 225 at 298216-
`
`300219) A March/April 1993 publication in “The Current Opinion in Therapeutic
`
`Patents,” for example, discussed the benefits of quinazoline derivatives as receptor
`
`tyrosine kinase inhibitors, and disclosed preferred compounds including 4-(3'-
`
`methoxyanilino)quinazoline.
`
`(DTX-428) Another example is a June 1994 article by
`
`David Fry (“Fry”), a Parke-Davis scientist, entitled “Expert Opinion on lnvestigational
`
`Drugs” (hereinafter, the “Fry review article”).
`
`(DTX-354; D.l. 225 at 303:7-304:1) The
`
`Fry review article discussed epidermal growth factor receptor kinase as a target for
`
`cancer chemotherapy.
`
`(DTX—354) According to Heathcock, a person of ordinary skill in
`
`the art would have noticed the statements in the Fry review article that certain 4-AQs
`
`were the most potent inhibitors of the tyrosine kinase thus far to be revealed, and that
`
`Parke-Davis was currently working in this area.
`
`(D.l. 225 at 304:5-21)
`
`24. Fry subsequently published an article entitled “A Specific Inhibitor of the
`
`Epidermal Growth Factor Receptor Tyrosine Kinase” in the high-profile journal Science
`
`in August 1994 (hereinafter, the “Fry Science article”).
`
`(PTX-43; D.l. 225 at 301 :10-15)
`
`The Fry Science article disclosed a molecule called “PD 153035,” as labeled by Parke-
`
`Davis Pharmaceutical Research, having the following structure.
`
`15
`
`APOTEX EX. 1028-016
`
`

`
`
`
`(PTX—43 at fig. 1) Heathcock testified that this compound is the same as that in
`
`example 2 of the Barker ‘226 application, and that the Fry Science article indicated that
`
`it is both a very potent compound and is highly selective for EGFR.
`
`(D.|. 225 at 301 :2-
`
`303:6) Mylan argues that “[i]n view of the Fry Science article, [] Fry’s review article,
`
`and other valuable information, there was little, if any, doubt that the 4-AQS were the
`
`best place for a medicinal chemist to start making potent, selective EGFR inhibitors.”
`
`(D.|. 232 at 11)
`
`25. To this end, Mylan also argues that the Barker ‘226 application suggests
`
`compounds that were better EGFR inhibitors than others. Only thirteen specific
`
`compounds were claimed in the Barker ‘226 application; these thirteen compounds
`
`were disclosed in the specification among a list of 32 “specific preferred” compounds.7
`
`(D.|. 232 at 11; DTX—286 at 18, 58-62 (claims 7, 9); D.l. 225 at 311:21—312:5) The
`
`compound of example 51 was one of three compounds claimed in claim 9.
`
`(D.l. 225 at
`
`311210-14) The Barker ‘226 application did not disclose biological data for the
`
`compound of example 51.
`
`(Id. at 313:1-3) Biological data was only disclosed for five 4-
`
`7Stil| additional compounds were listed as “preferred” rather than “specific
`preferred” compounds according to the specification.
`
`16
`
`APOTEX EX. 1028-017
`
`

`
`AQ compounds.8 (DTX—286 at 21) Heathcock explained that this disclosure is
`
`.
`sufficient to show the reader that this whole class of compounds is good .
`[T]hey’ve selected examples [for which biological data was provided] with a
`variety of different substituents, and so that [] is the important message a
`medicinal chemist would take from this set of data.
`It would not at all be
`
`.
`
`presumed to be all the biological data they had. You would naturally assume that
`they had tested a lot more than just five[‘’] compounds. And there was no reason
`to think that they had picked out their best five compounds to illustrate with
`biological data. For one thing, I think none of these five compounds were listed
`in the claims, and at least three of them were not even called specific preferred
`compounds of the invention.
`I would take this, and I think a person of ordinary
`skill in the art would take this data to be representative ofthe family.
`
`(D.|. 225 at 409:9-410:5)
`
`26. Heathcock also testified that, of the 105 compounds actually made, between
`
`75 and 80 examples had a methyl (alkyl) group at the 3' position of the molecule, “and a
`
`fairly large number, 15 or so, had a halogen or some other substituent at the 3'
`
`position.” (Id. at 310:7-18) It is his opinion, therefore, that “medicinal chemists would
`
`notice that alkenes and alkynes were omitted right after alkyl [groups] in [the
`
`specification’s] definitions,” and “would take the other clues from the [Barker] ‘226
`
`[application] to decide, well, if I’m going to put .
`
`.
`
`. an alkene and alkyne in this. .
`
`. aniline
`
`position, what should I use for the quinazoline?” (Id. at 310223-31 1 :4) Looking at the
`
`Barker ‘226 application to determine what the inventors regarded as the best, a
`
`medicinal chemist would “swap out whatever [he] had in the aniline ring and put in an
`
`8“[B]y way of example,” |C5O data was provided for three tests on: 6,7-
`dimethoxy-4(3'-methy|anilino)quinazoline; 6,7-dimethoxy-4-(35
`triflouromethy|ani|ino)quinazoline; 6-acetamido-4-(3'-methylanilino)quinazoline; and 7-
`(2-hydroxyethoxy)-6—methoxy—4—(3'—methylani|ino)quinazoline.
`(DTX—286 at 21:23-30)
`
`9It is unclear why Heathcock refers to five compounds. As noted previously,
`Mylan asserts in its post—tria| papers that there were only four exemplified; the court has
`also identified four compounds on the cited page of the Barker ‘226 application.
`
`17
`
`APOTEX EX. 1028-018
`
`

`
`aniline that had this alkynyl group or the alkenyl.” (Id. at 31144-9)
`
`27. The debated substituent (on the aniline ring) is the R2 position. The Barker
`
`‘226 application provides that the R2 group may be hydrogen, hydroxy, halogeno,
`
`triflouromethyl, amino, nitro, cyano, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di[(1-
`
`4C)alkyl]amino, (1-4C)a|kylthio, (1-4C)alkylsulphiny| or (1-4C)a|kylsulphonyl.”‘° (DTX-
`
`286 at 3:50-52, 4:30-32, 4:46-51) Claim 1 also requires that each R2 is one of these
`
`groups.
`
`(Id. at 59:49-51) The specification provides suitable values for R2 in various
`
`combinations, for example, “[a] suitable value for R‘ or R2 when it is (1-4C)a|kyl is, for
`
`example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, E-butyl or E-buty|[.]” (Id. at
`
`5:11-13) In sum, the Barker ‘226 application names alkyl groups for R2 - the relevant
`
`radical of an alkane, or a hydrocarbon substituent having only single bonds. As
`
`Heathcock explained, however, the specification stops short of naming alkene (a
`
`hydrocarbon substituent having a carbon to carbon double bond) or alkynes (a
`
`hydrocarbon substituent having a triple bond between two carbon atoms) for the R2
`
`position. Ethynyl (HCEC-), the substituent in erlotinib corresponding to the R2 position in
`
`the Barker ‘226 application, is an alkynyl group.
`
`(D.|. 226 at 405:20—21)
`
`28. Mylan refers to the foregoing as a “gap” in the coverage of the Barker ‘226
`
`application. According to Heathcock, “if you are trained as an organic chemist, which a
`
`medicinal chemist would be, in many cases .
`
`.
`
`. you’re going to do a double-take,
`
`because right after alkyl, something could be there that isn’t[:] alkenyl and alkyny|[,]”
`
`despite the inclusion of other more complicated substituents. “[T]hat would be
`
`‘°(1-4C) means that you can have one, t