PATENT
`Attorney Docket No. 07385.0042~00000
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Request for Supplemental
`Examination of:
`
`U.S. Patent No. 6,346,532
`
`Inventors: Tatsuya MAR.UYAMA et al.
`
`Issued: February 12, 2002
`
`For: AMIDE DERIVATIVES OR SAL TS
`THEREOF
`
`)
`)
`) Group Art Unit: Not Yet Assigned
`)
`) Examiner: Not Yet Assigned
`)
`)
`)
`) Confirmation No.: Not Yet Assigned
`)
`)
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Commissioner:
`
`Request For Supplemental Examination
`Of U.S. Patent No. 6,346,532
`
`Astellas Pharma, Inc. (hereinafter "Astellas"), is the owner of the entire right, title
`
`and interest of U.S. Patent No. 6.,346,532 ("the '532 patent"). The patent issued on
`
`national stage Application No. 09/529,096 ("the '096 application") based on PCT
`
`Application No. PCT/JP98/04671, filed October 15, 1998, claiming the benefit of
`
`Japanese Patent Application No. Hei 9-285778, filed October 17, 1997.
`
`I.
`
`§ 1.61 O{al
`
`The required fee of $16,860 is submitted herewith, which includes the $4,400.00
`
`filing fee, the $12, 100.00 reexamination fee, and a document size fee of $360.00,
`
`Astellas understands that if no reexamination is ordered, the $12, 100.00 reexamination
`
`fee will be refunded. Please charge any additional required fees or apply any credits to
`
`Deposit Account No. 09~0619.
`
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`In re Request for Supplemental
`Examination of USP 6,:146,532
`Attorney Docket. No. 0"7385.0042-00000
`
`II.
`
`Identification of the Number of the Patent for Which
`§ 1.6j9{bH1 }:
`Supplemental Examination is Requested
`
`Supplemental examination under 35 U.S.C. § 257 and 37 C.F.R. §§ 1.60'1-1 .625
`
`is requested for claims 1-14 of the '532 patent.
`m.
`
`§.j.610{b1{2}: A List of Items of Information that are Requested to be
`Considered, Reconsidered, or Corrected
`
`The following is a list of the iterns of information tr1at are requested to be
`
`considered:
`
`1.
`
`2.
`
`3.
`
`4,
`
`5,
`
`6,
`
`7,
`
`U.S. Patent No. 0,346,532 ("the '532 patent")
`
`those disclosed
`including
`for compounds
`Table of testing data
`Examples 1-113 of U.S. Patent No. 6,346,532 ("Testing Data Table")1
`;
`
`in
`
`Materials for Astellas R&D Meeting. Subcomrnittee on Development
`Theme Establishment,
`titled "YM178/Discont.inuation of Development
`Theme for Diabetes Mellitus," dated October 27, 2003 ("R&D Meeting
`Materials);
`
`YM 178 in Type 2 Diabetes Mellitus 1 "18~CL003 Study Report ("Study
`Report");
`
`Yamanouchi BAN Compound Evaluation System ("R&D Flowchart") with
`English-language translation;
`
`Yamanouchi Monthly Research Progress Repoit dated April 26, 1995
`("Monthly Progress Report") with English-language translation;
`
`the prosecution history of U.S. Patent Application
`Excerpts of
`the U.S. National Stage of PCT/JP98/04671,
`filed
`No. 09/529,096,
`October 15, 1998, that resulted in U.S. Patent No. 6,:346,5:-32 ("the
`Prosecution File History");
`
`1 The Testing Data Table also contains data for three compounds that are not
`exemplified in the '532 patent (a) BAN-371A (cornpound number 6), which is the free
`base equivalent of BAN~371 (compound number 5), whict1 is exemplified in Example
`041; (b) BAN-371 B (compound number 7), which is the racemic equivalent of BAN-371:
`and (c) BAN-371 C (compound number 8), which is the S-enantiomer equivalent of BAN-
`371.
`
`2
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`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042-00000
`
`8.
`
`9.
`
`Japanese Patent Application Kokai Publication No. H 10-218861, "Novel
`Phenethano! Derivative m Salt Thereof," published August 18, 1998, and
`certified English-language translation thereof ("JP '861 ");
`
`Blin, N. et al., "Structural and Conformational Features Determining
`Selective Signal Transduction in the ~3-Adrenergic Receptor," Molecular
`Pharmacology, 44:1094-1104 (1993) ("Biin");
`
`10.
`
`PCT Publication WO 94/18161, published 18 August 1994 ("WO '161");
`
`11.
`
`Thornber, C.W., "!sosterisrn and Molecular Modification in Drug Design,"
`Chem. Soc. Rev. 18:56:3-.. 580 (1979) (''Thornber");
`
`12.
`
`Declaration by Dr. Tetsuo Matsui under 37 C.F.R § 1.132 ("Matsui Dec.").
`
`IV,
`
`§ 1,61 O(b}{3i: A List Identifying Prior or Concurrent Post~Patent and
`Trademark Office Proceedings
`Involving
`the Patent
`for which
`Supplemental Examination is Being Requested
`
`/-\request for a Certificate of Correction under 37 C.F.R. §§ 1.322 and 1.323 was
`
`filed on April 17, 2002. The resulting Certificate of Correction was granted on July 13,
`
`2002.
`
`An Application for Extension of Patent Term under 35 C.F.R. § 156 of the '532
`
`Patent was filed on August 21, 2012. This application is currently pending.
`
`There are no other prior or concurrent proceedings involving the '532 patent.
`
`V.
`
`.§ 1.61.!)fb)(4}: An Identification of Each Claim of the Patent for Which
`Supplemental Exmnination is Requested
`
`Supplemental examination is requested for each of the claims 1-14 of the '532
`
`patent
`
`3
`
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`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042~00000
`
`VI.
`
`§ 1 &.1P1bj{5}: A Separate, Detailed Explanation of the Relevance and
`Manner of Applying Each Item of Information to Each Claim of the Patent
`for Which Supplemental Examination is Requested
`
`A surnrnary of the claimed subject matter and a detailed explanation of the
`
`relevance and manner of applying each item of information to each claim of the patent
`
`for which supplemental examination is requested is provided below.
`
`A.
`
`Summary of Claimed Subject Matter
`
`The '532 patent (Item of Information No.1) discloses and claims phenettianol
`
`amide derivatives represented by general formula (I) below, or salts thereof:
`
`Ring "B" in formula (I) is a l1eteroaryl group, which may be unsubstituted or substituted
`
`and is optionally fused with a benzene ring, "X" may be a bond, or a lower alkylene or
`
`an alkenyiene, both of which may be unsubstituted or substituted with hydroxy or a
`
`lower alkyl group, or Xis a carbonyl or a group represented by-NH-, and when Xis a
`
`lower alkylene group which is substituted with a lower alkyl group, a carbon atom of the
`
`ring B optionally bonds with the lower alkyl group so that a ring is formed. "A" may be a
`
`lower aikylene or a group represented by -lower alkylenewO-, R1a and R1
`
`b may be the
`
`same or different and each may be a hydrogen atom or a lower alkyl group. R2 may be
`
`a hydrogen atom or a halogen atom. "Z" is a group represented by =CH-····-" (See claim
`
`1.)
`
`4
`
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`In re Request for Supplemental
`Examination of' USP 6,346,532
`Attorney Docket No. 0"7385.0042-00000
`
`Claims 2-5 and 9 cover phenethanol derivative compounds represented by
`
`general formula (I), which are narrower in some respect compared to the compounds
`
`represented by general formula (I) as recited in claim 1.
`
`Claim 6 recites the following nine species of phenethanol amide derivatives that
`
`fall within the scope of claim 1:
`
`'*
`
`•
`
`( R )-4 '-[2-[ (2-Hyd roxy-2-phenylethyl )am i no]ethyi]-2·-·pyrid i necarboxya n i I ide,
`
`(R)-2-[1-(4-chlorobenzyl)-·1 H--irnidazol-2-yl)-4'-[.2-[(2-hydroxy-2-
`
`phenylethyl)amino]ethyl]-acetanilide,
`
`•
`
`(R)-2-[1-(3 ,4-dichiorobenzyl)-1 H-tetrazol-5-yl]-4'-[2-[(2-hydroxy-2-phenyl
`
`ethyl)amino]ethyl]acetanilide,
`
`•
`
`( R )-2-(2-am i noth iazol-4-yl )-4 '-[2-(2-hyd roxy-2-ph enylethyl )amino ]ethyl]
`
`acetanilide,
`
`'*
`
`'*
`
`•
`
`'*
`
`'*
`
`(R)-2-(2 .. benzyi .. 1 H-·1,2,4-triazol-3-yl)-4'-[2-[(2-hydroxy-2-phenylethy!)-
`
`arnino]ethyl]acetanilide,
`
`(R)-2-(2-aminopyridin-6-yi)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]
`
`acetanilide,
`
`(R)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyridyl) acetanllide,
`
`(R )-4 '-[2-[ (2-hyd roxy-2-phenylethyl )-amino ]ethyl )-2-( 2-pyrazi nyl)
`
`acetani!ide,
`
`(R)-4'-[2.-[{2-hydroxy-2-phenylethyl)amino]ethyl)-2-(2-pyrimidinyl)-
`
`acetanilide.
`
`5
`
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`

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`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042-00000
`
`Claims 7, 8, and 10~12 recite compositions comprising at least one compound as
`
`claimed in claim 1 -6.
`
`Claim 13 recites a method for treating diabetes mellitus comprising administering
`
`to a patient an amount of a compound as claimed in claim 1.
`
`Claim 14 recites a method for treating obesity comprising administering to a
`
`patient an amount of a compound as claimed in claim 1.
`
`The '532 patent states that the compounds of the invention have selective
`
`stimulative action to human fh·rnceptor, i.e., they are p3-adrenergic receptor-specific
`
`agonists. ('532 patent at col. 2, II. 28-29, col. ·12, II. 9··11.) The '532 patent also states
`
`that it was known that ~-adrenaline receptors are classified into f31, P2, and p3 subtypes.
`
`('532 patent at col. 1, IL 44-47.) Moreover, the '532 patent explains that stimulation of
`
`the P1··receptor causes an Increase in heart rate, that stimulation of the ~2-receptor
`
`stimulates decomposition of glycogen in muscles, whc·m~by synthesis of glycogen is
`
`inhibited, causing action such as muscular tremor, and that stimulation of the ~3-
`
`receptor shows anti-obesity and an anti-hyperglycemia action (such as decrease in
`
`triglyceride, decrease In cholesterol. and increase in HDL-cholesterol). ('532 patent, col.
`
`1, IL 46-54.)
`
`The •5:12 patent states that, due to their selective stimulating action to ~:1-
`
`receptors, the compounds of the invention are useful for the therapy of diabetes
`
`mellitus, having both an insulin secretion-promoting action and an insulin sensitivity-
`
`potentiating action, and further having anti-obesity and anti-hyperlipemia actions. ('532
`
`patent, coL 2, II. 31-37.) The '532 patent states that the selective hurnan ~;i-receptor
`
`stimulating action of the compounds of the Invention was ascertained through ~1, ~z.
`
`6
`
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`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042-00000
`
`and p3 testing. ('532 patent, col. 12, ii. 9-12.) Specifically, the patent teaches that the
`
`human ~3-receptor stimulating action was investigated using an SK-N-MC cell system
`
`(cells in wi1icll human fh-receptor and human ~1-receptor were permanently expressed
`
`were purchased) while human ~1r and P1-stimulating actions were Investigated using a
`
`CHO cell system (cells in which each of human ~2- and f31--receptors was compulsorily
`
`expressed were purchased). ('532 patent, col. 11, II. 56-63.)
`
`Tile '532 patent specification concludes with 113 examples, each, witll the
`
`exception of example 107, disclosing a different phenethanol derivative compound of
`
`the claimed invention. Exarnple 41 discloses a compound having the chemical formula
`
`(R)-2-(2-arninothiazol-4-yl)-4'-[2-(2-hydroxy-2-phenylethyl)amino]-ethyl]acetanilide
`
`dihydrochioride, w~1ich is encompassed by claims
`
`'l-14 of the '532 patent. The
`
`compound of Example 41 is a dihydrochloride salt of a compound commonly known as
`
`mirnbegron, which is an FDA-approved drug sold under the trademark, MYRBETRIQ™.
`
`None of the current claims is limited to cover only Astellas' commercialized
`
`product, mirabegron. Should
`
`the Patent and Trademark Office order ex parle
`
`reexamination of the claims of the '532 patent in connection with this request for
`
`supplemental examination, Astellas intends to amend the claims of the '532 patent to
`
`cover only mirabegron and its salts.
`
`B.
`
`Sumrnary of Relevance to Claimed Subject Matter
`
`1.
`
`The Testing Data Table (Item of Information No. 2)i Matsui Dec.
`(item of information No, 12), R&D Meeting Materials {Item of
`Information No. 3) and Study Report {Item of Information No. 4)
`
`As discussed above, the '532 patent states that the compounds of the invention
`
`are useful as therapeutic agents for treating diabetes mellitus. (See, e.g., tl1e •5:12
`
`7
`
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`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042-00000
`
`patent, col. 2,
`
`IL 3T-41; col. 9,
`
`IL 62~63; Abstract.) However,
`
`the commercial
`
`embodiment of the claimed invention, mirabegron, is not approved for treating diabetes
`
`meilitus. Instead, MYRBETRIQTM received FDA approval in June 2012 for the treatment
`
`of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and
`
`urinary frequency.
`
`The Testing Data Table, discussed in more detail below, shows that the inventors
`
`conducted a series of in vitro and in vivo studies before October 15, 1998, trie date on
`
`which the PCT application leading to the issuance of the '532 patent was filed. From H1e
`
`results of these preliminary studies mirnbegron showed promise as an anti-diabetic
`
`medicine, and based upon the available information, the FDA approved commencement
`
`of Phase I clinical trials to determine appropriate dosages of mirabegron for Phase II
`
`clinical trials to assess efficacy for treating diabetes mellitus. (See Matsui Dec. ljl 7; see
`
`also Testing Data Table, Compound BAN 3"71, Cols. 4-9.) Based on the r·esuits of the
`
`ensuing limited Phase Ila clinical trials, performed after the '532 patent issued, the then
`
`current assignee, Yamanouchi Pharmaceutical Co., Ltd. (hereinafter "Yamanouchi"'), 2
`
`decided that mirabegron did not demonstrate sufficient efficacy to be a commercially
`
`competitive drug for the treatment of diabetes mellitus, and so decided it would not
`
`pursue diabetes mellitus as an indicated use. (See Matsui Dec. 1[ 8; see also, e.g., R&D
`
`Meeting Materials at p. 13 ("The results of the phase Ila study of [mirabegron]
`
`administered at a dose of 200 mg in the fed state could not confirm the efficacy of
`
`2 Yamanouchi Pharmaceutical Co,, Ltd. is a predecessor company that through a
`merger with another pbarmaceutical cornpany formed Astellas, the current. assignee.
`
`8
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`In rlf'.~ Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042-·00000
`
`[mirabegron] in terms of the primary end points (HbA1c and fasting blood glucose
`
`level")).)
`
`Despite the decision to discontinue the development of mirabegron for the
`
`treatment of diabetes mellitus, Yamanouchi conducted a detailed analysis of the results
`
`of the Phase Ila cllnical study prior to the discontinuance of the project, which revealed
`
`that mirabegron did have some efficacy in certain patient subgroups. (See Matsui Dec.
`
`1[ 9; see also, e.g., the Study Report. that states:
`
`Some efficacy was found only when HbA1c at baseline was above 7% (data from
`central
`laboratory;
`local data T-8%);
`responses of HbA 1 c and FPG
`to
`[mirabegron] were rnainly found for female patients.
`
`Changes in HbA 1 c were mainly detected in young patients; in elderly no
`difference between [rnirabegron] and placebo could be found, even when
`baseline H bA 1 c was taken into account
`
`(Study Report at p. 1 ·1, slides 21-22).)
`
`Because the Phase Ila clinical trial results were not available until mid-2003, this
`
`information was not before the Patent and Trademark Office during prosecution of the
`
`'532 patent, which issued on February 12, 2002. Because no compound encompassed
`
`by claims 1-14 proved sufficiently efficacious to be considered commercially competitive
`
`for the treatment of diabetes mellitus, which was the principal utility described in the
`
`specification, this information may be considered to raise a substantial new question of
`
`patentability with respect to those claims, and in particular with respect to claim 13.
`
`9
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`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042--00000
`
`2.
`
`The Testing Data Table (Item of Information No. 2), Matsui Dec.
`(Item of Information No. 12), R&D Flowchart {Item of
`Information No. 5), Monthly Progress Report
`(Item of
`Information No. 6), and the Prosecution File History (Item of
`Information No. 7)
`
`As confirmed by one of the inventors of the '532 patent, Dr. Matsui, the Testing
`
`Data Table was compiled from laboratory notebooks and other developmental materials
`
`generated by the inventors of the '5:32 patent (Matsui Dec, ,-r 6,) The table presents
`
`certain testing data for all of the claimed compounds disclosed in Examples 1-106 and
`
`108~113 of the '532 patent. 3 Colurnn 1 of the Testing Data Table provides the internal
`
`Yamanouchi code (BAN) number for each of the compounds. Column 2 provides the
`
`example number from the '532 patent. Column 3 provides the chemical structure of the
`
`compound. Columns 4-6 provide the ~-adrenergic receptor data for each cornpound as
`
`pD2 values and IA% ("Intrinsic Activity" as compared to isoproterenol - numbers in
`
`parentheticals) using the CHO screening test. Column 7 provides ED:~o data for several
`
`of the compounds based on hypoglycemic studies in KK mice. Column 8 provides ~h·
`
`adrenergic receptor data determined using the SK~N-MC screening test Column 9
`
`provides the test report dates for these data in columns 4-8. (Matsui Dec. 1[ 6.)
`
`As discussed above, the '532 patent states that the compounds of the invention
`
`selectively stimulate the p3 receptor. For example, column 2, lines 28~30, teach that the
`
`compounds of the invention "show a selective stimulating action to [:h-receptors, leading
`
`to accomplishment of the present invention." Similarly, column 2, line 37, states that U1e
`
`Insulin secretion-promoting action and insulin sensitivity-potentiating action of the
`
`3 As mentioned above, the compound of Exarnple 107 is not a phenethanoi derivative
`and, therefore, is not covered by the claims of the '532 patent
`
`10
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`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042-00000
`
`compounds of the invention are due to their "selective stimulating action to ~3-
`
`receptors." Likewise, column 9,
`
`lines 61-62, discuss
`
`the "selective p3-receptor
`
`stimulating action" of the compounds of the invention. Further, column 10, lines 7-9,
`
`state that "[t]he p3-receptor stimulating action of the compound of the present invention
`
`is selective to p3-receptors in human being." In addition, column 10, lines 61-65, state
`
`that the compounds of the invention have "been ascertained to be selective to ~:i-
`
`receptors .... "
`
`The '532 patent states that p3-receptor stimulating action for the compounds of
`
`the invention was ascertained by comparing the effects of the claimed compounds on
`
`the P1, ~2. and f33 receptor subtypes using cells expressing human-type receptors. (See
`
`col. 11, I. 56 to coL 12, I. 11; see 1.":Jlso col. 10, II. 61-65.) Specifically, stimulating
`
`activities of the compounds were investigated by incubating cells expressing each of the
`
`13~adrenergic receptor subtypes with the compounds of the invention and measuring
`
`production of cyclic adenosine monophosphate (cAMP), which is a byproduct of r3-
`
`adrenergic receptor activation. (Id.)
`
`As stated in the '532 patent, the intensity of action of each compound against the
`
`[31, i32, and f33··rnC(~ptors was cornpared by calculating the pD2 value and the maximum
`
`value (IA%i where the maximum reaction of 10-6M isoproterenol, a non-selective ~~-
`
`agonist, was defined as 100%) from the resulting dose-reaction curve. (See the '532
`
`patent at coL 11, I. 56 to col. 12, I. 11.)
`
`11
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`In re Request for· Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042-00000
`
`a. Not All of the Claimed Compounds of Examples 1-106 and
`108N113 of the '532 Patent Were Shown To Have Greater Ila
`Receptor Activity Compared to Either 131 or Jh Receptor
`Activity
`
`As can be seen in the Testing Data Table, cols. 4-6, the compounds of Examples
`
`1-106 and 108-113 that fall within the scope of claim 1-14 of the '532 patent were tested
`
`using the CHO P1, ~2, and ~3-receptor stimulation screening tests. Although ail of the
`
`compounds tested showed some level of ~3-receptor agonist activity, depending on
`
`whether the IA% or pD2 test results are used, a number of the claimed compounds
`
`exhibited ~h-receptor agonist activities that were not as high as the corresponding ~1·· or
`
`r'h-receptor agonist activities. (Matsui Dec. 1[ 1 O; see also table below.) For example,
`
`although the compound o'f Example 1, designated BAN 404, covered by at least claims
`
`1, 2, 6, 7, 8, 9, 10, 12, 13, and 14 of the '5:t2 patent, showed Ps-receptor agonist activity
`
`greater than B4-receptor agonist activity in both the IA% and pD2 tests, it showed p3 ..
`
`receptor agonist activity k~ss than ~2-receptor agonist activity. (Id.; see also Testing
`
`Data Table, Compound BAN 404, cols. 4-6.) Because these initial CHO screening data
`
`provided in the Testing Data Table, wr1ich
`
`indicate that some of the compounds
`
`encompassed by claims ·1-14 may not have ~~i-receptor agonist activity selectivity over
`
`both the ~r- and ~rreceptors as taught in the '532 patent, were not before the Patent
`
`and Trademark Office during prosecution of the '532 patent, this information may be
`
`considered to raise a substantial new question of patentability with respect claims 1-·14
`
`of the '532 patent.
`
`12
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`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07:~85.0042-00000
`
`b, Not All of the Claimed Compounds of Examples 1~106 and
`Internal
`1Ot:M13 of the '532 Patent Met Yamanouchi 1s
`Criteria For Further Development
`
`As of time the '096 application was filed, and up to the time the '532 patent
`
`issued, Yamanouchi utiliz.ed certain internal screening criteria to determine whether a
`
`compound has sufficient 133-receptor agonist activity and selectivity to warrant further
`
`evaluation for potential eventual submission as an anti-diabetic drug. (Matsui Dec 1[ 11.)
`
`As the R&D Flowchart shows, in general, before a candidate compound qualified for-
`
`further evaluation, Yamanouchi's
`
`initial
`
`internal screen stated
`
`that a candidate
`
`compound should have an IA test result for ~3-receptor agonism of greater than 0.6 (m
`
`60%) and a pD2 value for the ~3-receptor of greater than 6.5, while at the same time
`having IA test results for P1- and ~~rreceptor agonlsm of less than 0.2 (or 20%). (Id.; see
`
`also R&D Flowchart.)
`
`The following data, excerpted from the Testing Data Table, provide examples of
`
`the claimed compounds that did not meet Yamanouchi's initial r33-receptor selectivity
`
`and/or activity criteria set forth in the R&D Flowchart:
`,-----ch'a_i1.#'···l······sAFf#
`Exam·r;T0··:if····r·····cam-?ou~~-~;ereci··0y----·r--:~ ~ ~~-··--- -----~~-:--~-~------!
`···--~-............. JJ~.!~ .. ~-1 ........... PP.~ .. P..1 .... J
`l ................ ___ J_ .... __ .................. ----------------------------------------------j:_ ____________ ................
`i
`I
`I 58.1
`!
`13
`377
`-
`110
`1,2,7,8,9,10,13,14
`5.23
`!
`I
`I
`I
`i
`i
`!
`i 22.7
`5.65
`i
`i
`j
`1 ............................. J, ............................... _____ , ................................ ~-~----·--·----·---------·----''--------------------------------------------1----....... ?. 7
`<4 ........... -l
`!
`!
`i
`·19
`390
`105
`I
`1,2,7,8,9.10,13,14
`24
`0.3
`I
`I 2a
`I
`I
`-
`I
`!
`s.9
`............................ ________________________________________ l ......................... ____ ............................... J ......... J.?.
`--- ............ ~:-~ ......... ..]
`I
`l
`i
`i
`18
`88
`5.9
`~i9£)
`1,2,7,8,9,10,13,14
`j
`j
`!
`I
`50
`4.2
`:
`,
`........ ------- ............... t ..... ,,---------;:------------------------------ ......... --- ---i--.. --..... ?.9 ........... +.... <4_& ...... ...i
`3
`18
`-
`5.9
`27
`4.2
`!
`,., ,, ,,,,,.,,,.,,,,.,,,,.,,,.,_,.,.,,.,., ,.,,.,.,.,,,,,,,,.,.,,,,,,,.,,, .. .,.,,.,.,,.,,,,.,,,, ............. '" ,,, J "' '" .? ...... ,,.,.,,,,,_m•~~,'o_, .,. •
`13
`
`1
`r ............................... 1 ...
`22
`.--
`.--
`
`j
`
`,,., .--
`
`i_
`
`21
`
`---
`
`---
`
`--
`
`---
`
`l 1,2,7,8,9,10,13,14
`
`i
`
`-
`
`396
`---
`---
`---
`
`PT0_00001107
`
`Sawai Ex. 1007
`Page 13 of 495
`
`

`

`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042~00000
`-----ctlarHr-- ------a"Ji:·i\J·"ff···T···Ex~ini?Te-·trr·--cfom-?otl'ri·a··c;·o·v:0·r:0-crsy i 1A o/~---p·:r·;·----·r;-0~--~·3·--···
`I
`I
`I IA% 13:2
`I pD:i 132
`Claims
`·-----------~-------~- .~--........ J .. ____________________________________ .L............................
`. ............................ LJ~-~0 .. 13.~----- ...... P.R.~Jlt._,,
`I
`I
`398
`9G
`1,2.7,8,9,10,13,'14
`27
`5.6
`23
`I
`I
`-
`17
`5.9
`-----------··--------···--···· ................................ L ........ ____________________ .. ____ J __________________________ ~-------------w---------------··--···"-···--·· .......... Jt~---i ............ ::1 .......... J
`I
`I 1,2,6,l,8,9,10,12,13,14
`I
`I
`!
`I
`i
`
`2
`
`1,2,7,8,9,10,13,14
`
`29
`
`404
`
`1
`
`'
`
`I
`
`I
`I
`
`10
`25
`
`5.1
`5.4
`<4
`I
`I
`6.o
`11
`I
`s.a
`I
`18
`. ....................... L .......... 9 ............. L .. ________ ~.:1: ........... .J
`.............................. -------------------------------- ---------------------------------··--··· ............................
`I
`I
`32
`1,2,3A,7,8,9,10,13,14
`I
`I
`I
`I
`I
`I
`I
`I
`i
`!
`.................. L .......... 1 .. 1 .......... L ......... § .. :~ .......... ..
`............................................................... f .......................................................... , .. ,--------
`i
`i
`36
`411
`101
`1,2,7,8,9, 10, '13, 14
`6.2
`37
`'
`0
`4
`I
`5
`1 5 .
`I
`.......... ., ............ .,., .. """"'"'"'~-~-- ---~-
`................................... _________ J __________ J_§l __________ _L ____ ,, .... ~.:§ .......... ..
`I
`I
`I
`6.9
`39
`414
`1,2,?,8,9,10,13,14
`55
`89
`'
`6 6
`I 2s
`I 5:6
`I
`............................. , ................................ __. ....... , .. , ...........................
`·------------------------··--···--···--···--···--········""'"''''"'''"'''"'''""'""'"""""-'------~-----------.I
`i
`I
`I
`1,2,3,4,7,8,9,10,13,14
`14
`e.2
`49
`435
`36
`I
`I
`!
`!
`27
`5 3
`!
`I
`I
`I
`<4
`I
`5
`i
`i <5.0
`I
`i
`27
`I
`I
`i
`19
`5.4
`I
`I
`I
`6
`<4
`I
`!
`·~···,..._,_,.,,~, .................................. Tn~n•THHTHHTnHTnH•-~~··~n•TnTTn.,...,...,._.,,,...,. ___ .......,._ ---~· ······~~ .. .., . . . . . . . . . . . . . . . . . , . . . . . . . . . . . , •• ········---·----------"·-··--------------~,:.---------------------------~----····•»•••»•••»•'-'"'''"'
`I
`I
`I
`41
`6.3
`53
`·
`447
`a
`1,2,7,8,9,10,13,·14
`~:~
`I ~~
`I
`I
`-------------------------------~--------------------------------~---------------------------------------'-, ------···••»•••»••·······--···--·--............................ --~-~"''''~~-''''~'"'~''~'~'''t·~., ......•••. ,,,,,,,,,,,,,,,,,.
`55
`455
`I
`I
`18
`1,2,7,8,9,10,13,14
`I
`49
`5.8
`I
`I 31
`I 5.9
`.
`i
`I
`I
`· ............ 5·1............ .., ....... 47'a--···------··---------··· .. 1·7r3·--·--···- -----··-·:r;:r1:·1f9:-~ra:·:r:f1-~r-.. ----r·w----tfa ... --.. ---r------··--5-:{f ··---··-..
`69
`4.4
`i
`!
`49
`6.4
`"'""'""'""'""'"''""""'"""""""""""""""''"""''"""';"""''"""''"""''"""''"""''"""''"""''"""'',""''"""''"'''"'''''''''''''''''''"''"'''''''''"'''"'''"'''"'"""'"'..!"'""'":1.1 .... m,.,,,.,,"'"''"1':g,.,.,,,,,,,,,
`1,2,3A,5,7,8,9,10,'11,13,14 i
`I
`68
`7.1
`·
`109
`548
`•·
`15
`
`••-••••-••••--•••-••••--·•••••• ""'''"""''"'"'""""'"'''" ''"'''"''''"'''"'''""'"'''""'J,.,WN#eN"-"'""""""''"''''''''''W"'''''''"'''"'''"'''"'"'l'''"'''"'''9.''"'""''J
`
`30
`
`405
`
`407
`
`11
`
`---~-
`35
`
`o
`
`-------------'-"·"""""""-"'"----------·--'----------------------------------······················--···· .. ···-------------~------~-
`111
`1,2,7,8,9,10,13,·14
`
`40
`37
`3
`32
`53
`
`1
`
`I
`
`6.4
`6.4
`<4
`5.6
`5,5
`
`''"'""''"""'"'"""'"'"'i
`
`l '
`
`'
`
`112
`
`.~--------------------------··-' ··--························----~---······························"''"~ .... ,,.,,,,.
`
`50
`
`440
`
`37
`
`1,2,3A, 7,8,9,10, 1 ~i.14
`
`.... ........ -
`
`I
`
`I
`I
`
`.. ,~ ...................................................... ~ ................................... .J
`
`_
`
`............................................................... l ......................................... • ............... .,.,., .. ~~~------'-1 _____ ~-~----········J ...... ----~:_1 __________ _
`
`14
`
`PT0_00001108
`
`Sawai Ex. 1007
`Page 14 of 495
`
`

`

`In re Request for Supplemental
`Examination of USP 6,346,532
`Attorney Docket No. 07385.0042-00000
`
`Thus, there are 17 claimed compounds shown in the table above that did not
`
`satlsfy Yarnanouchi's internal criteria for further development based on either the pD2 or
`
`IA% values. (Matsui Dec. 1Til ·12-·1 s.) This ~h-receptor selectivity and activity data, and
`
`Yamanouchi's internal criteria for evaluating it, were not before the Patent and
`
`Trademark Office during prosecution of the '532 patent Because these examples do
`
`not satisfy Yamanouchi's internal ~3-receptor selectivity and/or activity criteria for some
`
`compounds that are within the scope of claims 1-14, they may be considered to raise a
`
`substantial new question of patentability with respect to claims 1-14 of the '532 patent
`
`c.
`
`The '532 Patent Did Not Correctly Identify the Assay
`to Determine
`for
`the Claimed
`J33wSelectivity
`Used
`Compounds
`
`As discussed above, the inventors determined ~3 -·stimulating action of the
`
`compounds of the invention by comparing the effects of the claimed compounds on the
`
`P1, P2. and
`
`fl3-receptor subtypes using cells expressing human-type receptors.
`
`According
`
`to
`
`the specification, an SK-N-MC cell system comprising human
`
`neuroblastorrn:.1 cells permanently expressing the human B1 .. and ~h-receptor was used
`to assess p3 activity, and CHO cell systems comprising Chinese hamster ovary cells
`
`permanently 1axpressing either the human Pr or !32-receptors were used to assess f31
`
`and f32 activities. (See the '532 patent, col. 11, I. 56 to col. 12, L 11.)
`
`As shown by the information provided in column 9 of the Testing Data Table,
`
`however, none of the claimed compounds of Examples 1-106 and 108 .. ,113 in the '532
`
`patent was tested for ~3-stirnulatlng action using the SK-N-MC cell system until after the
`
`October 15, 1998, filing date of the international application that led to the '532 patent
`
`(i.e., PCT/JP98/04671). (See also Matsui Dec. 'fl 15.) As reflected in the R&D Meeting
`
`15
`
`PT0_00001109
`
`Sawai Ex. 1007
`Page 15 of 495
`
`

`

`In re Request for Supplemental
`Examination of USP 6,:346,532
`Attorney Docket No. 07385.0042-00000
`
`Materials, the Inventors assessed the 133-selectivity of mirabegron, and all of the claimed
`
`compounds disclosed in examples 1-106 and 108-113 of the '532 patent, using the
`
`CHO cell system. (See R&D Meeting Materials at p. 3; see also Matsui Dec.1! 15.) The
`
`CHO cell system used to assess the p3-agonist activity of the claimed compounds
`
`disclosed in Examples 1-106 and 108-113 was essentially the same as the CHO cell
`
`system used by the inventors to assess the ~·1- and i3z-agonist activity of those same
`
`compounds, except the CHO cells permanently expressed the human ~~1-receptors only.
`
`(See Matsui Declaration at ,-r 16.)
`
`The SK-N--MC cell system referred to in the specification was used by the
`
`inventors to evaluate potential anti-diabetic compounds that were synthesized before
`
`the compounds encompassed by the claims of the '532 patent, and it was considered
`
`competent as a basis for assessing the p3-selectivity of those compounds. (Matsui Dec,
`
`,J 17,) A switch was made to the CHO cell system because the gene for the single
`
`human ~:)-receptor became available and could be used to construct a CHO assay,
`
`whereas the cells in the SK-N-MC cell system also contained a f\1-receptor and n:~quired
`
`the use of a ~1-receptor blocker to mask any 131 effects, (Id.; see a/so the '532 patent,
`
`coL 11, line 67 - col. 12, line 2,) The inventors obtained the gene for the f\3-receptor
`
`from a foreign patent office based upon a foreign patent filing. (Matsui Dec. 1'[ 19.) They
`
`did not refer to the j:b-CHO cell systern assay in the instant patent application because
`
`of a concern that using the ~a gene in an experimental assay might be asserted to be an
`
`act of patent infringement in Japan. (Id.)
`
`The Monthly Progress Report in which the inventors evaluated and co