IN THE UNITED STATES PATENT AND TRADEMARKOFFICE
`
`Application of:
`
`Jeffrey B. Etter
`
`Confirmation No.:
`
`5370
`
`Serial No.:
`
`12/466,213
`
`Art Unit:
`
`1623
`
`Filed:
`
`For:
`
`May 14, 2009
`
`Examiner:
`
`Lawrence E. Crane
`
`ORAL FORMULATIONS OF
`CYTIDINE ANALOGS AND
`METHODS OF USE THEREOF
`
`Attorney Docket
`(CAM No.:
`
`9516-847-999
`501872-999847)
`
`AMENDMENT AND RESPONSE
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`In responseto the non-finaloffice action mailed August 1, 2011, Applicants
`respectfully submit the following amendments and remarks for the Examiner’s consideration
`
`and entry into the record.
`
`Amendments to the Specification begin on page 2 ofthis paper.
`
`Amendments to the Abstract begin on page 4 of this paper.
`
`Amendmentsto the Claimsare reflected in the listing of the claims that
`begins on page 5 ofthis paper.
`
`Remarks begin on page 12 ofthis paper.
`
`Applicants hereby authorize any required fees, including a one-month time
`extension fee of $150 and a fee of $180 forfiling a Supplemental Information Disclosure
`Statement, to be charged to Jones Day Deposit Account No. 50-3013.
`
`SDI- 108640v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0710
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0710
`
`

`

`AMENDMENTSTO THE SPECIFICATION
`
`Please make the following amendmentsto the as-filed specification:
`
`Please replace the first paragraph on page | with the following amended paragraph:
`
`This application claims priority to U.S. Provisional Patent Application Nos.
`[0001]
`61/053,609, filed May 15, 2008, which is now expired; 61/201,145, filed December 5, 2008,
`which is now expired; and 61/157,875, filed March 5, 2009, which is now expired, the
`contents of each of which are incorporated by reference herein in their entireties.
`
`Please replace paragraphs 35-37 on page 11 with the following amended paragraphs:
`
`Figure 4A represents PD data from an individual patient (Subject 02008, 80
`[0035]
`year old male, RAEB-1) collected during a multiple dose escalation study. The patient was
`
`dosed with azacitidine Formulation #3, 240 mg. Platelets (K/L); and Hgb (g/dL)-ANE
`
`<4},andRelativeBMBlast(%)are plotted versus sampling dates over the course ofthe
`study in Figure 4A. Figure 4B represents PD data from an individual patient(Subject 02008
`80year old male, RAEB-1) collected during a multiple dose escalation study. The patient
`was dosed with azacitidine Formulation #3, 240 mg. ANC (K/uL) and Relative BM Blast
`(%) are plotted versus sampling dates over the courseof the study in Figure 4B.
`
`Figure 5A represents PD data from an individualpatient (Subject 02007, 76
`[0036]
`year old male, CMML)collected during a multiple dose escalation study, The patient was
`dosed with azacitidine Formulation #3, 240 mg. Platelets (K/uL); andHgb (g/dL)-ANG
`
`Cs/+b),andRelativeBMBlast(9) are plotted versus sampling dates over the course ofthe
`study inFigure SA. Figure 5B represents PD data from an individual patient (Subject 02007,
`76year old male. CMML)collected duringa multiple dose escalation study. Thepatient was
`dosed with azacitidine Formulation #3,240mg. ANC (K/uL) and Relative BM Blast (%)are
`plotted versus sampling dates over the course ofthe study in Figure 5B,
`
`SDI-108640v1
`
`2m
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0711
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0711
`
`

`

`Figure 6A represents PD data from anindividual patient (Subject 02004, 61
`[0037]
`year old male, MDS, MDACC)collected during a multiple dose escalation study. The
`patient was dosed with azacitidine Formulation 1, 120 mg. Platelets (K/L); andHgb (g/dL),
`
`ANC-ds+h),andRelativeBMBlast4)are plotted versus sampling dates over the course of
`the study in Figure 6A. Figure 6B represents PD data from an individualpatient(Subject
`02004,61year old male, MDS,MDACC)collected duringamultiple dose escalation study.
`The patient was dosed with azacitidine Formulation 1. 120 mg. ANC(K/uL)and Relative
`BM Blast (%) are plotted versus sampling dates over the course of the studyin Figure 6B.
`
`SDI-108640vi
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0712
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0712
`
`

`

`AMENDMENTS TO THE ABSTRACT
`
`Please make the following amendmentsto the as-filed abstract:
`
`ABSTRACT
`
`The present disclosure provides pharmaceutical compositions comprising cytidine
`analogs, for example, 5-azacytidine or decitabine, for oral administration, wherein the
`compositionsrelease the cytidine analog,for example, 5-azacytidine or decitabine,
`substantiallyin the stomach. Also provided are methods of treating diseases and disorders
`using the oral formulations provided herein.
`
`SDI1-108640v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0713
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0713
`
`

`

`AMENDMENTS TO THE CLAIMS
`
`The following listing of claims will replaceall prior versions. and listings, of
`claims in the application.
`
`Listing of the Claims
`
`(Currently amended) A pharmaceutical composition for oral administration
`1.
`comprising a therapeutically effective amountofa cytidine analog 3-azaeytidine and at least
`one pharmaceutically acceptable excipient, wherein the composition is an immediate release
`tablet or an immediate release capsule, and the cytidine analog is 5-azacytidine or decitabine
`
`
`
`2.
`
`(Canceled).
`
`(Currently amended) The composition of claim 1, whiehis-aen-enteric-coated
`3.
`wherein the composition does not comprise an enteric coating.
`
`(Currently amended) The composition ofclaim 1, whieh wherein the
`4,
`composition is a tablet.
`
`(Currently amended) The composition ofclaim 1, whieh wherein the
`5.
`composition is a capsule.
`
`(Currently amended) The composition ofclaim 1, whichurther-comprises-an
`6.
`wherein the pharmaceutically acceptable excipient is selected from mannitol, microcrystalline
`cellulose, crospovidone, and magnesium stearate.
`
`7.
`enhancer.
`
`(Original) The composition of claim 1, which further comprises a permeation
`
`(Currently amended) The composition of claim 7, wherein the permeation
`8.
`enhanceris d D-alpha-tocopheryl polyethylene glycol 1000 succinate.
`
`SDI-108640v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0714
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0714
`
`

`

`(Currently amended) The composition of claim 8, wherein the d D-alpha-
`9.
`tocopheryl polyethylene glycol 1000 succinate is presentin the formulation at about 2% by
`weight relative to the total weight ofthe formulation.
`
`(Original) The composition of claim 1, which is essentially free of a cytidine
`10.
`deaminase inhibitor,
`
`(Original) The composition of claim 1, which is essentially free of
`11.
`tetrahydrouridine.
`
`(Currently amended) The composition of claim 1, which further comprises an
`12,
`
`additionaltherapeutic a therapeutically effective amount ofa second active agent.
`
`(Currently amended) The composition ofclaim 1, wherein the amount of5-
`13.
`azacytidine or decitabine is at least about 40 mg.
`
`(Currently amended) The composition of claim 1, wherein the amount of5-
`14.
`azacytidine or decitabine is at least about 400 mg.
`
`(Currently amended) The composition ofclaim 1, wherein the amount of5-
`15.
`azacytidine or decitabineis at least about 1000 meg.
`
`(Currently amended) The composition of claim 1, which has been shown to
`16.
`achieves an area-under-the-curve value ofat least about 200 ng-hr/mL following oral
`administration to a test subject.
`
`(Currently amended) The composition ofclaim 1, which has been shown to
`17.
`achieves an area-under-the-curve value of at least about 400 ng-hr/mL following oral
`administration to a test subject.
`
`(Currently amended) The composition of claim 1, which has been shownto
`18.
`achieves a maximum plasma concentration ofat least about 100 ng/ml. following oral
`administration to a test subject.
`
`SD1-108640v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0715
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0715
`
`

`

`(Currently amended) The composition of claim 1, which has been shown to
`19,
`achieves a maximum plasma concentration of at least about 200 ng/mL following oral
`-
`administration to a test subject.
`
`(Currently amended) The composition of claim 1, which has been shownto
`20.
`achieves a time to maximum plasmaconcentration of less than about 180 minutes following
`oral administration to a test subject.
`
`(Currently amended) The composition ofclaim 1, which has been shownto
`21.
`achieves a time to maximum plasmaconcentration ofless than about 90 minutes following
`oral administration to a test subject.
`
`(Currently amended) The composition of claim 1, which has been shown to
`22.
`achieves a time to maximumplasma concentration ofless than about 60 minutes following
`oral administrationto a test subject.
`
`(Currently amended) A method for treating a-subjecthaving one or more
`23.
`symptoms ofa disease associated with abnormal cell proliferation, comprising orally
`administering to the a subject in need thereof a pharmaceutical composition comprising a
`therapeutically effective amountof a cytidine analog 5-azaeytidine and at least one
`pharmaceutically acceptable excipient, wherein the composition releases the cytidine analog
`3-azaeytidine substantially in the stomach following oral administration to the subject, the
`disease associated with abnormalcellproliteration is a cancer or a hematologic disorder, and
`the cytidine analog is 5-azacytidine or decitabine.
`
`24,
`syndrome.
`
`25.
`leukemia.
`
`(Original) The method ofclaim 23, wherein the disease is myelodysplastic
`
`(Original) The method of claim 23, wherein the disease is acute myelogenous
`
`26.
`
`(Original) The method of claim 23, wherein the disease is non-small-cell lung
`
`cancer.
`
`27,
`
`(Original) The method ofclaim 23, wherein the disease is ovarian cancer.
`
`SDL-108640v1
`
`-7~
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0716
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0716
`
`

`

`28.
`
`29,
`
`30.
`survival.
`
`(Original) The method of claim 23, wherein the disease is pancreatic cancer.
`
`(Original) The method ofclaim 23, wherein the disease is colorectal cancer.
`
`(Original) The method ofclaim 23, which results in improved overall
`
`(Currently amended) The method ofclaim 23, wherein the method further
`31.
`
`comprises co-administering to the subject in need thereof an-additienaltherapeutic a
`therapeutically effective amount ofa second active agent.
`
`(Original) The method ofclaim 23, wherein the composition is an immediate
`32,
`release composition.
`
`(Original) The method ofclaim 23, wherein the composition further
`33,
`comprises a permeation enhancer.
`
`(Currently amended) The method of claim 33, wherein the permeation
`34,
`enhanceris d D-alpha-tocopheryl polyethylene glycol 1000 succinate,
`
`(Currently amended) The method of claim 34, wherein the d D-alpha-
`35.
`tocophery! polyethylene glycol 1000 succinate is present in the formulation at about 2% by
`weightrelative to the total weight of the formulation.
`
`a 3
`
`(Original) The method ofclaim 23, wherein the method further comprises not
`6.
`co-administering a cytidine deaminase inhibitor with the cytidine analog.
`
`37.
`dosage form.
`
`(Original) The method ofclaim 23, wherein the composition is a single unit
`
`(Currently amended) The method ofclaim 23, wherein the composition does
`38,
`not comprise an enteric coating isnen-enteric-coated.
`
`39,
`
`(Original) The method ofclaim 23, wherein the composition is a tablet.
`
`SD1-108640v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0717
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0717
`
`

`

`40.
`
`(Original) The method ofclaim 23, wherein the composition is a capsule.
`
`(Currently amended) The method of claim 23, wherein the pharmaceutically
`Al.
`acceptable compesition-furthercomprises-an excipient is selected from mannitol,
`microcrystalline cellulose, crospovidone, and magnesium stearate.
`
`(Currently amended) The method of claim 23, wherein the amount of5-
`42.
`azacytidine or decitabineis at least about 40 mg.
`
`(Currently amended) The method ofclaim 23, wherein the amount of 5-
`43.
`azacytidine or decitabineis at least about 400 mg.
`
`(Currently amended) The method ofclaim 23, wherein the amountof5-
`44,
`azacytidine or decitabine is at least about 1000 mg.
`
`(Currently amended) The method of claim 23, which has been shownto
`45.
`achieves an area-under-the-curve value ofat least about 200 ng-hr/mL following oral
`administration to the a test subject.
`
`(Currently amended) The method ofclaim 23, which has been shownto
`46,
`achieves an area-under-the-curve value ofat least about 400 ng-hr/mL following oral
`administration to the a test subject.
`
`(Currently amended) The method ofclaim 23, which has been shownto
`47.
`achieves a maximumplasma concentration ofat least about 100 ng/mL following oral
`administration to the a test subject.
`
`(Currently amended) The methodof claim 23, which has been shownto
`48.
`achieves a maximum plasma concentration ofat least about 200 ng/mL following oral
`administration to the a test subject.
`
`(Currently amended) The method ofclaim 23, which has been shownto
`49.
`achieves a time to maximum plasma concentration of less than about 180 minutes following
`oral administration to the a test subject.
`
`SDI-108640v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0718
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0718
`
`

`

`(Currently amended) The method ofclaim 23, which has been shownto
`50.
`achieves a time to maximum plasma concentration of less than about 90 minutes following
`oral administration to the a test subject.
`
`(Currently amended) A pharmaceutical composition comprising a
`51.
`therapeutically effective amount ofa cytidine analog 5-azaeytidine and at least one
`pharmaceuticallyacceptable excipient, wherein the composition is for treating a disease or
`disorder associated with abnormalcell proliferation, wherein the composition is an immediate
`release tablet or an immediate release capsule prepared for oral administration, wherein the
`disease or disorder associated with abnormalcell proliferation is a cancer or a hematologic
`disorder, and wherein the cytidine analogis 5-azacytidine or decitabine and-whereinthe
`
`
`
`(Currently amended) The pharmaceutical composition ofclaim 5 1, wherein
`52.
`the amountof5-azacytidine or decitabine is about 40 mg, about 400 mg, or about 1000 mg.
`
`(Currently amended) The pharmaceutical composition of claim 51, wherein
`53.
`the composition is-prepared has been shownto achieve an area-under-the-curve value ofat
`least about 200 ng-hr/mL or 400 ng-hr/mL following oral administration to a test subject.
`
`(Currently amended) The pharmaceutical composition of claim 51 , wherein
`54.
`the composition is-prepared has been shownto achieve a maximum plasma concentration of
`at least about 100 ng/mL or 200 ng/mL following oral administrationto a test subject.
`
`(Currently amended) The pharmaceutical composition ofclaim 51, wherein
`55.
`the composition is-prepared has been shownto achieve a time to maximum plasma
`concentration of less than about 60 minutes or 90 minutes after being administered to a test
`subject,
`
`56.
`
`(Canceled).
`
`(Currently amended) The pharmaceutical composition of any one ofclaims
`57.
`51 to 55, wherein the composition is prepared for oral administration in combination with an
`additionaltherapeutic a therapeutically effective amount ofa second active agent.
`
`
`SD1-108640v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0719
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0719
`
`

`

`(Original) The pharmaceutical composition of any one of claims 51 to 55,
`58.
`whereinthe disease or disorder is myelodysplastic syndromeor acute myelogenous leukemia.
`
`(Currently amended) The pharmaceutical composition of any one of claims
`59,
`51 to 55, wherein the compositionis a tablet
`singleunitdesaseform.
`
`(Currently amended) The pharmaceutical composition of any one of claims
`60.
`51 to 55, wherein the composition is a-tableter a capsule.
`
`(Currently amended) The pharmaceutical composition of any one of claims
`61.
`51 to 55, wherein the eempesitienturthercomprisesan pharmaceuticallyacceptable
`excipient is selected from mannitol, microcrystalline cellulose, crospovidone, and magnesium
`stearate.
`
`62-65. (Canceled).
`
`66.
`azacytidine.
`
`(New) The composition of claim 1, wherein the cytidine analog is 5-
`
`67.
`
`68.
`
`69.
`
`(New) The composition ofclaim 1, wherein the cytidine analog is decitabine.
`
`(New) The method of claim 23, wherein the cytidine analogis 5-azacytidine.
`
`(New) The method ofclaim 23, wherein the cytidine analog is decitabine.
`
`(New) The pharmaceutical composition ofclaim 51, wherein the cytidine
`70.
`analog is 5-azacytidine.
`
`(New) The pharmaceutical composition of claim 51, wherein the cytidine
`71.
`analog is decitabine.
`
`SDI-108640v1
`
`-l1l-—
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0720
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0720
`
`

`

`REMARKS
`
`Amendments to the Specification
`
`The specification is amendedat page 1, first paragraph, to recite the current
`status of provisional applications. No newmatter is added.
`
`The specification is amendedat page 11, paragraphs 35-37, to provide
`separate descriptions for formal Figures 4A, 4B, 5A, 5B, 6A, and 6B. Support is found, for
`example, in the as-filed specification at page 11, paragraphs 35-37, andthe as-filed Figures
`4—6. No new matter is added.
`
`Entry of the amendmentsto the specification is respectfully requested.
`
`Amendments to the Abstract
`
`The abstract is amendedtorecite “5-azacytidine or decitabine” as exemplary
`embodiments of a cytidine analog. Support is found throughoutthe as-filed specification,
`including, for example, at page 17, paragraph 75; and page 19, paragraph 79. No newmatter
`is added.
`
`Entry of the amendments to the abstractis respectfully requested.
`
`Claim Amendments
`
`Claims 1, 3-55, 57-61, and 66—71 are pending in this application. Claims2,
`56, and 62-65 are canceled without prejudice to Applicants’ right to pursue the subject matter
`recited therein in one or moredivisional, continuation, and/or continuation-in-part
`applications.
`
`Claims 1, 3-6, 8-9, 12-23, 31, 34-35, 38, 41-55, 57, and 59-61 are amended
`without any intention of disclaiming any equivalents thereof.
`
`Claim | is amendedto recite, inter alia, “a cytidine analog,” “at least one
`pharmaceutically acceptable excipient,” “an immediate release tablet or an immediate release
`capsule,” and “the cytidine analog is 5-azacytidine or decitabine.” Support is found, for
`example, at page 6, paragraph 17; pages 14-15, paragraphs 63—64; page 17, paragraph 75;
`
`SDI-108640v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0721
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0721
`
`

`

`page 19, paragraph 79; and pages 36-37, paragraph 121 of the as-filed specification.
`
`Claims 8—9 and 34—35 are amendedtorecite, inter alia, “D-alpha.” Support is
`found, for example,at the original claims 8—9 and 34—35.
`
`Claims 12, 31, and 57 are amendedtorecite, inter alia, “a therapeutically
`effective amountof a second active agent.” Support is found, for example, at page 52,
`paragraph 155, lines 1-5 of the as-filed specification.
`
`Claims 13-15, 42-44, and 52 are amendedto recite, inter alia, “decitabine.”
`Support is found, for example, at page 17, paragraph 75; and page 19, paragraph 79 ofthe as-
`filed specification.
`
`Claims 16-22, 45—50, and 53—55 are amendedto recite, inter alia, “has been
`shownto achieve” and “test subject” as recommended bythe Examiner.
`
`Claim 23 is amended. Support is found, for example, at page 6, paragraph 17;
`page 12, paragraph 55; page 17, paragraph 75; page 19, paragraph 79; pages 36-37,
`paragraph 121; pages 60-61, paragraphs 171 and 173; and pages 64-65, paragraph 182 ofthe
`as-filed specification.
`
`Claim 51 is amended. Support is found, for example, at page 6, paragraph 17;
`pages 14—15, paragraphs 63-64; page 17, paragraph 75; page 19, paragraph 79; pages 36-37,
`paragraph 121; pages 60-61, paragraphs 171 and 173; and pages 64-65, paragraph 182 ofthe
`as~filed specification.
`
`Claims 59 and 60 are amended. Support is found, for example, at the original
`
`claim 60.
`
`subject matter.
`
`Claims 3—6, 38, 41, and 61 are amended to more clearly recite the claimed
`
`Claims 66-71 are added. Support is found, for example, at page 17, paragraph
`75; and page 19, paragraph 79ofthe as-filed specification.
`
`No new matteris introduced. Applicants respectfully request consideration
`and entry of the claim amendments.
`
`Applicants respectfully submit that the pending claimsare allowable for at
`least the following reasons.
`
`SDI-108640v1
`
`-13—
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0722
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0722
`
`

`

`A.
`
`Objections to the As-Filed Abstract and Specification
`
`On pages 2-3 of the Office Action, the as-filed abstract and specification are
`objected to. Without acquiescingto the propriety ofthe objections, and solely to expedite
`prosecution, the abstract and paragraphs | and 35-37 ofthe specification have been amended.
`Applicants respectfully request the objections be withdrawn.
`
`B.
`
`Claim Rejections Under 35 U.S.C. § 101
`
`Claims 62-65 are rejected under 35 U.S.C. § 101 allegedly “because the
`claimedrecitation of a use, without setting forth any steps involved in the process.” Office
`Action, at page 3. Without acquiescingto the propriety of the rejection, and solely to
`expedite prosecution, claims 62-65 have been canceled without prejudice. Applicants
`respectfully request the rejection to claims 62-65 be withdrawn.
`
`Claims 16-22, 45—50, and 53—55 are rejected under 35 U.S.C. § 101. The
`Office Action alleges that “the claim of an in vivo result in the present tense implies
`ownership ofthe host treated.” Office Action,at page 3. Applicants respectfully disagree
`because claims 16-22, 45—50, and 53—55 are directed to pharmaceutical compositions and
`methods oftreatment, which are clearly patentable subject matter under 35 U.S.C. § 101 as
`mandated by the statute and controlling case law. Contrary to the allegations of the Office
`Action, the claims do not imply any ownership ofa treated subject. However, solely to
`expedite prosecution of the present application and without prejudice, claims 16-22, 45-50,
`and 53-55 have been amended according to the Examiner's suggestion. See Office Action,at
`page 4. Applicantsrespectfully request the rejection to claims 16-22, 45-50, and 53-55 be
`withdrawn.
`
`Cc.
`
`Claim Rejections Under 35 U.S.C. § 112, First Paragraph
`Claims 23—S0 and 62-65 are rejected under 35 U.S.C. § 112, first paragraph,
`as allegedly not enabled. Specitically,it is alleged that “the specification, while being
`enabled for the treatment ofa limited number of neoplastic disease conditions (see the non-
`prospective disclosures of Examples 1~7), does not reasonably provide enablement for the
`effective treatmentofall other ‘diseases associated with abnormal cell proliferation,’
`including at least cancers of pancreas(instant Example 11 is entirely prospective), liver and
`
`SDI-108640v1
`
`-14—
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0723
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0723
`
`

`

`It is further alleged that the analysis of Wands factors as set
`brain.” Office Action, at page 4.
`forth in the Office Action showsthat undue experimentation would be required for practicing
`the claimed methods. Office Action, at pages 4-5, Applicants respectfully disagree with
`each of these allegations and respectfully request reconsideration and withdrawalofthe
`rejections on the ground of enablement.
`
`The test for enablement is whether oneskilled in the art could make or use the
`invention based on the disclosures of the specification coupled with information known in the
`art at the timeoffiling without undue experimentation. See,e.&., US. v. Telectronics Inc.,
`857 F.2d 778, 785 (Fed. Cir. 1988). The test is not whether any experimentation is necessary,
`but whetherit is undue. See, e.g., Inre Angstadt, 190 U.S.P.Q. 214, 219 (C.C.P.A. 1976).
`Factors to determine whether undue experimentationis required are set forth in In re Wands.
`In re Wands, 858 F.2d 731, 737 (Fed.Cir. 1988). As the Federal Circuit explained in Wands,
`routine screening does not amount to undue experimentation. /d at 736. “A considerable
`amount ofexperimentation is permissible,ifit is merely routine.” /d. at 737.
`
`In addition, “a specification disclosure which contains a teaching of the
`manner and process of making and using an invention... must be taken as being in
`compliance with the enablement requirement. .
`. unless there is a reason to doubt the
`objective truth ofthe statements,” and thus, the Office has the initial burden to establish a
`reasonable basis to question the enablement provided for the claimed invention. M.P.E.P.
`§ 2164.04, citing In re Wright, 999 F.2d 1557, 1562 (Fed. Cir. 1993),
`
`In view ofthese well-settled legal principles, Applicants respectfully submit
`that the analysis of Wandsfactors provided in the Office Action falls far short of meeting the
`initial burden ofestablishing a legally sufficient basis to question the enablementof the
`instant application. Thus, the rejections on the ground ofenablement are legally improper
`and should be withdrawn.
`
`Applicants respectfully point out that claims 23—50! are enabled becausethe
`specification “contains a teaching of the manner and process of making and using an
`invention in terms which correspond in scopeto those used in describing and defining the
`subject matter sought to be patented.” M.P.E.P. § 2164.04. For example, the specification
`teaches that 5-azacytidine or decitabine can modulate the activity of DNA methyltransferases,
`
`' Claims 62-65 have been canceled withoutprejudice.
`
`SDI-108640v1
`
`-|[5—
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0724
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0724
`
`

`

`therebyrestoring normal functions of morphologically dysplastic, immature hematopoietic
`cells and cancercells. (e.g., Specification, at paragraph 11.) Indeed, 5-azacytidine and
`decitabine have been approved for intravenous(IV) or subcutaneous (SC) administration to
`treat myelodysplastic syndromes (MDS). (e.g., Specification,at paragraphs 9 and 11-13.)
`However, at the time ofthe application, oral delivery of 5-azacytidine or decitabine has
`proven difficult. (e.g., Specification, at paragraph 13.) In this regard, the specification
`describesin detail various embodiments of oral formulations of cytidine analogs, such as S-
`azacytidine or decitabine, that release the cytidine analog substantially in the stomach
`following oral administration, and providesspecific working examples of formulations that
`were shownto achieve significant drug exposure in the plasma ofasubjectafter oral
`administration. (¢.g., Specification, at paragraphs 108-154 and Examples 1-6.)
`Furthermore, the specification teaches, inter alia, that one or more symptomsof cancers and
`hematological disorders can be treated by modulators of DNA methyltransferase, such as 5-
`azacytidine or decitabine. (e.g., Specification, at paragraphs 11-12 and 196-205.) The
`specification further describes detailed methods of using the oral formulations provided
`therein to treat one or more symptomsofa disease associated with abnormalcell
`proliferation, including cancers and hematologic disorders. (¢.g., Specitication, at paragraphs
`170-206 and Examples 4-12.) In view ofthe disclosure ofthe instant specification, those
`skilled in the art can makean oral formulation of 5-azacytidine or decitabine, fully guided by
`the detailed description and specific examples provided, and orally administer the
`formulation to a subject in need thereofto treat one or more symptoms of a cancer ora
`hematological disorder, for example, by reversing abnormal DNA methylation in the subject.
`Therefore, it is clear that the application provides sufficient guidanceto allow those of
`ordinary skill in the art to make and use the claimed invention without undue
`experimentation.
`
`However, the Office Action contendsthat the analysis of Wands factors as set
`forth therein showsthat undue experimentation would be required for practicing the claimed
`methods. Applicants respectfully disagree. The instant claimsrelate to treating one or more
`symptomsofparticular diseases, such as cancers and hematologic diseases, using an oral
`formulation of 5-azacytidine or decitabine which releases the 5-azacytidine or decitabine
`substantially in the stomach following oral administration. As explained above, the
`specification provides ample guidance to a person of ordinary skill in the art to practice the
`claimed invention without undue experimentation. Indeed, when analyzing the Wands
`
`SDI-108640v1
`
`-16—
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0725
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0725
`
`

`

`factors, the Office Action contends that the “[t]he treatment of neoplastic disease by the
`administration ofan effective amount of 5-azacytidine to a hostin need thereofis very well
`knownin the art. . .” and “[i]Jn view ofthe substantial and relevant teachings of ... cited
`documentspresently of record disclosing that 5-azacytidine has neoplastic activity supports
`the view thatthis art area is at least somewhatpredictable.” Office Action, at pages 4-5.
`Thus, it appears that the Office Action concedesthat 5-azacytidine possesses anti-neoplastic
`activity and may be usedto treat neoplastic diseases. Yet, the Office Action goes onto allege
`that “non-prospective exemplifications appear to end at Example 7,” and “[t]he small number
`of instant exemplifications suggests that the instant disclosure has enabled only a very limited
`numberof disease treatments wherein 5-azacytidine is administered as the active ingredient.”
`Office Action, at page 5.
`In this regard, Applicants respectfully point out that compliance
`with the enablement requirement does not turn on whether an example is disclosed. M.P.E.P.
`§ 2164.02.
`It is respectfully reminded that the claims are presumed to be enabled where the
`specification “contains a teaching of the manner andprocess of making and using [the
`claimed] invention.” Inre Wright, 999 F.2d at 1562. Sucha teachingis clearly provided by
`the current specification, and no evidenceto the contrary is provided by the Office.
`Furthermore,as explained above,the instant application provides detailed descriptions or
`specific examples on how to use oral formulations of 5-azacytidine or decitabine to treat
`cancers or hematologic disorders.
`In view ofthe guidance providedinthe instant application,
`the state of the art and the level of one ofordinary skill at the time of the application, the
`required experimentation, if any, to practice the subject matter of claims 23-50 would be
`merely routine. In other word, no undue experimentation by one skilled in the art is needed
`to practice the claimed methods.
`
`Therefore, Applicants respectfully submit that the rejections under 35 U.S.C.
`§ 112, first paragraph, on the ground of enablement should be withdrawn.
`
`D.
`
`Claim Rejections Under 35 U.S.C. § 112, Second Paragraph
`
`Claims 1-65 are rejected under 35 U.S.C. § 112, second paragraph,as
`allegedly indefinite. Office Action, at pages 5-7. Without acquiescing to the propriety of the
`rejections, and solely to expedite prosecution, claims 1, 3-6, 8-9, 12, 23, 31, 34-35, 38, 41,
`51,57, and 61 have been amended without prejudice. Applicants respectfully request the
`rejections for alleged indefiniteness be withdrawn.
`
`SDI-108640V1
`
`-17-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0726
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0726
`
`

`

`E.
`
`Claim Rejections Under 35 U.S.C. § 102
`
`Claims 1—65are rejected under 35 U.S.C. § 102(b) as allegedly being
`anticipated by U.S. Patent No. 7,189,740 to Zeldis (hereinafter “the ‘740 Patent”). Office
`Action, at pages 7-8. In particular, the Office Action refers to the ‘740 Patentat claims | and
`7-11; column 25, lines 8-48; and column7, lines 16-21; and alleges that the ‘740 Patent
`teaches “pharmaceutical compositions of5-azacytidine” and “second active ingredient”
`including “conventional therapy for MDS.” Office Action, at pages 7-8. The Office Action
`also refers to Beers et al. (The Merck Manual of Diagnosis and Therapy, 2006, pages 1114—
`111