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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria1 Virginia 22313- 1450
`wwwnsptogov
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`APPLICATION NO.
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` F ING DATE
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`FIRST NAMED INVENTOR
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`ATTORNEY DOCKET NO.
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`CONF {MATION NO.
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`13/372,426
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`02/13/2012
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`Matvey E. LUKASHEV
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`2159.3210002/JMC/MRG/U—S
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`5998
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`53644
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`7590
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`10/12/2012
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`stNE, KESSLER, Gomsmmmx, 13.1.1.0
`1100 NEW YORK AVE., N.W.
`WASHINGTON, DC 20005
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`ART UNIT
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`1649
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`MAIL DATE
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`10/12/2012
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`ULM, JOHN D
`PAPER NUMBER
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`DELIVERY MODE
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`PAPER
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`Please find below and/or attached an Office communication concerning this application or proceeding.
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`The time period for reply, if any, is set in the attached communication.
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`PTOL—90A (Rev. 04/07)
`Page 1 of 11
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`Biogen Exhibit 2021
`Mylan V. Biogen
`IPR2018-01403
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`Page 1 of 11
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`Biogen Exhibit 2021
`Mylan v. Biogen
`IPR2018-01403
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`Office Action Summary
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`Application No.
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`Applicant(s)
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`13/372,426
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`Examiner
`JOHN ULM
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`LUKASHEV ET AL.
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`Art Unit
`1649
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`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address --
`Period for Reply
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`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE 3 MONTH(S) OR THIRTY (30) DAYS,
`WHICHEVER IS LONGER, FROM THE MAILING DATE OF THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR1. 136( a).
`In no event however may a reply be timely filed
`after SIX () MONTHS from the mailing date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`-
`- Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
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`Status
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`1)IZI Responsive to communication(s) filed on 03 August 2012.
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`2a)IZ| This action is FINAL.
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`2b)I:l This action is non-final.
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`3)I:I An election was made by the applicant in response to a restriction requirement set forth during the interview on
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`; the restriction requirement and election have been incorporated into this action.
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`4)|:l Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
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`closed in accordance with the practice under Exparte Quay/e, 1935 CD. 11, 453 O.G. 213.
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`Disposition of Claims
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`5)IZI Claim(s) His/are pending in the application.
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`5a) Of the above claim(s) _ is/are withdrawn from consideration.
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`6 I:I Claim s) _ is/are allowed.
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`18-37 is/are rejected.
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`is/are objected to.
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`are subject to restriction and/or election requirement.
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`Application Papers
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`10)I:I The specification is objected to by the Examiner.
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`11)|:| The drawing(s) filed on _ is/are: a)|:l accepted or b)I:l objected to by the Examiner.
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`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
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`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121 (d).
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`12)I:I The oath or declaration is objected to by the Examiner. Note the attached Office Action or form PTO-152.
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`Priority under 35 U.S.C. § 119
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`13)I:I Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
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`a)I:I AII
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`b)I:I Some * c)|:l None of:
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`1.I:I Certified copies of the priority documents have been received.
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`2.I:I Certified copies of the priority documents have been received in Application No. _
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`3.|:I Copies of the certified copies of the priority documents have been received in this National Stage
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`application from the International Bureau (PCT Rule 17.2(a)).
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`* See the attached detailed Office action for a list of the certified copies not received.
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`Attachment(s)
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`1) I] Notice of References Cited (PTO-892)
`2) D Notice of Draftsperson‘s Patent Drawing Review (PTO-948)
`3) IZI Information Disclosure Statement(s) (PTO/SB/08)
`Paper No(s)/Mai| Date 8/3/12.
`US. Patent and Trademark Office
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`4) D Interview Summary (PTO-413)
`Paper N°(5 )/Mai| Date. _
`5)I:I Notice of Informal Patent Application
`)6|:| Other:
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`PTOL-326 (Rev. 03-11)
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`Office Action Summary
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`Part of Paper No./Mai| Date 20121009
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`Page 2 of 11
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`Page 2 of 11
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`Application/Control Number: 13/372,426
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`Page 2
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`Art Unit: 1649
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`DETAILED ACTION
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`DETAILED ACTION
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`1)
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`Claims 18 to 37 are pending in the instant application. Claim 37 has been
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`added as requested by Applicant in the amendment filed 03 August of 2012.
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`2)
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`Any objection or rejection of record that is not expressly repeated in this
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`action has been overcome by Applicant’s response and withdrawn.
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`3)
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`The text of those sections of Title 35, U.S. Code not included in this action
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`can be found in a prior Office action.
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`Claim Rejections - 35 USC § 103
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`4)
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`Claims 18 to 37 are rejected under 35 U.S.C. 103(a) as being
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`unpatentable over the Joshi et al. patent publication (US 2003/0018072 A1) for those
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`reasons of record as applied to claims 1 to 36 in section 4 of the office action mailed 03
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`May of 2012. As stated therein, these claims are drawn to a method of treating multiple
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`sclerosis (MS) in an individual suffering therefrom by the daily oral administration
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`thereto of dimethyl fumarate or diethyl fumarate at a rate of 480 mg per day, which is
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`prima facie obvious in view of the Joshi et al. patent publication because Joshi et al.
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`fairly taught the treatment of M8 by the administration to an individual suffering
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`therefrom an effective amount of dimethyl fumarate, methyl ethyl fumarate and diethyl
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`fumarate. Whereas Joshi et al. does not anticipate the instant claims because it did not
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`disclose the specific treatment protocol recited therein, one of ordinary skill in the art
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`would have found it prima facie obvious to have engaged in that routine experimentation
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`needed to determine the optimal effective protocol for such treatment.
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`Page 3 of 11
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`Page 3 of 11
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`Application/Control Number: 13/372,426
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`Page 3
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`Art Unit: 1649
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`Applicant has extensively traversed this rejection essentially on the premise that
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`the claimed method produces particularly advantageous and unexpected results as
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`applied to individuals suffering from multiple sclerosis (MS). The unexpected and
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`advantageous results demonstrated for the claimed method relative to the other
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`embodiments that are disclosed in the instant specification are not in dispute. However,
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`neither those unexpected and allegedly advantageous results nor the particular
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`combination now claimed are described in the specification as filed.
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`In fact, the
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`demonstration that the now claimed combination is operable in not unexpected.
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`It is
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`Applicant’s discovery, subsequent to the filing of the instant application, that the majority
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`of embodiments described in the specification are inoperative that is unexpected. The
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`fact that dimethyl fumarate, methyl ethyl fumarate and diethyl fumarate can be
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`successfully employed to treat MS was not unexpected as of the filing date of the
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`instant application. The only aspect of the claimed invention that is absent from the
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`prior art is daily dosage, and the instant specification, as filed, disclosed no particular
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`advantage to the dosage of fumarate derivative recited in the instant claims.
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`The instant specification teaches the treatment of a plurality of neurological
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`diseases including those listed in paragraphs [0104] to [0106] therein, which states that
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`“neurological diseases suitable for the methods described herein include
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`neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's
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`disease, Alzheimer's disease, and Huntington's disease”, “MS”, “acute haemorrhagic
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`leucoencephalomyelitis, Hurst's disease, acute disseminated encephalomyelitis, optic
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`neuritis, Devic's disease, spinal cord lesions, acute necrotizing myelitis, transverse
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`Page 4 of 11
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`Application/Control Number: 13/372,426
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`Page 4
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`Art Unit: 1649
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`myelitis, chronic progressive myelopathy, progressive multifocal leukoencephalopathy
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`(PML), radiation myelopathy, HTLV-1 associated myelopathy, monophasic isolated
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`demyelination, central pontine myelinolysis, and leucodystrophy (e.g.,
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`adrenoleucodystrophy, metachromatic leucodystrophy, Krabbe's disease, Canavan's
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`disease, Alexander's disease, Pelizaeus-Merbacher disease, vanishing white matter
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`disease, oculodentodigital syndrome, Zellweger's syndrome), chronic inflammatory
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`demyelinating polyneuropathy (CIDP), acute inflammatory demyelinating
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`polyneuropathy (AIDP), Leber's optic atrophy, Charcot-Marie-Tooth disease”,
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`“polyneuritis and mitochondrial disorders with demyelination”. Nowhere does the
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`instant specification, as filed, disclose a particular advantage to applying the method
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`described therein to MS.
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`In addition, with respect to dimethyl fumarate (DMF) or monomethyl fumarate
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`(MMF), the text in paragraph [0116] of the specification taught that “an effective amount
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`can range from 1 mg/kg to 50 mg/kg (e.g., from 2.5 mg/kg to 20 mg/kg or from 2.5
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`mg/kg to 15 mg/kg)” and that “an effective dose of DMF or MMF to be administered to a
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`subject orally can be from about 0.1 g to 1 g per day, 200 mg to about 800 mg per day
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`(e.g., from about 240 mg to about 720 mg per day; or from about 480 mg to about 720
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`mg per day; or about 720 mg per day)”. Again, the specification, as filed, fails to
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`demonstrate, or even predict, any particular advantage to be realized from the
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`administration of a dosage of 480 mg per day of DMF or methyl ethyl fumarate (MEF) to
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`an individual suffering from MS. Applicant’s subsequent discovery that the vast majority
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`of dosages described in the specification are inoperative is the only unexpected result
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`Application/Control Number: 13/372,426
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`Page 5
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`Art Unit: 1649
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`that is supported by the evidence of record, and those embodiments are not the subject
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`of the instant claims.
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`Applicant’s assertion on page 9 of the response filed 03 August of 2012 that “the
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`results of the Phase 2 clinical study would have led one of ordinary skill in the art to use
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`a different, higher dose (i.e., 720 mg/day) rather than the dose required by the claimed
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`invention (i.e., 480 mg/day)” is not consistent with the express teachings of the instant
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`specification as cited above.
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`If one of ordinary skill was aware of these results then
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`Applicant was certainly aware of them, and yet, as discussed above, the specification
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`expressly teaches the daily administration of DMF or MMF “from about 0.1 g to 1 g per
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`day, 200 mg to about 800 mg per day (e.g., from about 240 mg to about 720 mg per
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`day; or from about 480 mg to about 720 mg per day; or about 720 mg per day”.
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`In
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`addition, the instant specification, as filed, fails to suggest any specific daily dosage of
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`DMF or MMF that had been shown or could reasonably be predicted to be effective in
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`the treatment of MS, in particular. The only dosages described in the specification were
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`identified therein as being applicable to the treatment of the whole variety of
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`neurological diseases recited in paragraphs [0104] to [0106].
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`It is a matter of law that a claimed invention must be patentable as of the
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`effective filing date of the application containing that claim. Applicant may not rely upon
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`subsequent discoveries made by themselves or others to complete the claimed
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`invention.
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`In the decision In re Lundberg, 117 USPQ 190, 1958, the CCPA held that
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`"advantages which are not disclosed in application cannot be urged as basis for
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`allowing claims". This rejection is not in conflict with the decision in in re Chu, 66 F.3d
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`Application/Control Number: 13/372,426
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`Page 6
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`Art Unit: 1649
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`292, 298-99, 36 USPQZd 1089, 1094-95 (Fed. Cir. 1995). The claimed subject matter
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`at issue in in re Chu (US Patent 5,567,394, Chu et al.) was distinguished from the most
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`closely related prior art by the placement of a catalyst at a particular position in an
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`apparatus for controlling emissions of a fossil fuel fired boiler. Evidence provided by
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`Applicant demonstrated addition undisclosed advantages that inherently result from that
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`placement. Whereas the Chu et al. application did not disclose certain unexpected
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`results obtained thereby, it clearly disclosed the criticality of placing the catalyst at the
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`particular position recited in the claims and the subsequently demonstrated advantages
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`were inherent to that element.
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`In the present case, the instant specification does not
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`disclose the criticality of the limitations of the now claimed treatment protocol nor does it
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`identify the claimed combination as being particularly advantageous, which
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`distinguishes the current fact pattern from that which was addressed by the court in in re
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`Chu. Applicant's discovery that the majority of embodiments disclosed in the
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`specification are inoperative hardly supports the patentability of those few embodiments
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`that have been subsequently discovered by Applicant to be operable.
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`5)
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`Claims 18 to 37 are are rejected under 35 U.S.C. 103(a) as being
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`unpatentable over the Schimrigh et al. publication (Euro. J. Neurol. 13(6):604-610, Jun.
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`2006) for those reasons of record as applied to claims 1 to 36 in section 5 of the office
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`action mailed 03 May of 2012. As indicated above, these claims are drawn to a method
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`of treating multiple sclerosis in an individual suffering therefrom by the daily oral
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`administration thereto of dimethyl fumarate or diethyl fumarate at a rate of 480 mg per
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`day.
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`Application/Control Number: 13/372,426
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`Page 7
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`Art Unit: 1649
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`The Schimrigh et al. publication has been relied upon because it described the
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`successful clinical treatment of human subjects suffering from multiple sclerosis by the
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`administration of fumaric acid esters, which include dimethyl fumarate, methyl ethyl
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`fumarate and diethyl fumarate, to those subjects. The Schimrigh et al. publication does
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`not anticipate the instant claims because it did not disclose the specific treatment
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`protocol recited therein. However, as indicated above, one of ordinary skill in the art
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`would have found it prima facie obvious to have engaged in that routine experimentation
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`needed to determine the optimal effective protocol for such treatment. Merely
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`determining the optimal conditions for practicing a prior art process, in the absence of
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`unexpected results, does not constitute a patentable inventive contribution. The
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`discovery that not all of the possible treatment protocols encompassed by the prior art
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`are operable is not unexpected. One of ordinary skill would not reasonably expect the
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`administration of dimethyl fumarate, methyl ethyl fumarate or diethyl fumarate to an
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`individual suffering from M8 at any and all dosage regimens to be operable. However,
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`identifying an optimal treatment protocol, including the identification of inoperable
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`regimens, requires nothing more than the routine practice of the art.
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`Applicant has traversed this rejection essentially on the premise that Schimrigh et
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`al. taught the administration of 1290 mg of fumarates a day. No effort has been made
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`to review Applicant’s mathematical analysis of Schimrigh et al. since, with respect to the
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`fumaric acid esters employed therein, the abstract of that publication expressly stated
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`that “[t]he study consisted of the following four phases: 6-week baseline, 18-week
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`treatment (target close of 720 mg/day), 4-week washout, and a second 48-week
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`Application/Control Number: 13/372,426
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`Page 8
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`Art Unit: 1649
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`treatment phase (target close of 360 mg/day)” (emphasis added). The Schimrigh et al.
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`abstract further expressly identified the treatment protocol described therein as an
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`“exploratory, prospective, open-label study”. As indicated by the text in the paragraph
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`entitled “Study Drug” on page 605 of that reference, the predominant active ingredient in
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`Fumaderm is the same dimethylfumarate recited in the instant claims. Therefore,
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`Applicant’s position that the Schimrigh et al. taught away from a dosage of 480 mg/day
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`of fumarate derivatives is not supported by the facts of record.
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`Response to Arguments
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`6)
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`Applicant's arguments filed 03 August of 2012, as well as the declarations
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`by Richard A. Rudick and Katherine Dawson under 37 CFR 1.132 that were filed 03
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`August of 2012, have been fully considered but they are not persuasive essentially for
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`those reasons given above.
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`Conclusion
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`7)
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`THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of
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`time policy as set forth in 37 CFR1.136(a).
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`A shortened statutory period for reply to this final action is set to expire THREE
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`MONTHS from the mailing date of this action.
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`In the event a first reply is filed within
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`TWO MONTHS of the mailing date of this final action and the advisory action is not
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`mailed until after the end of the THREE-MONTH shortened statutory period, then the
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`shortened statutory period will expire on the date the advisory action is mailed, and any
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`extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of
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`Application/Control Number: 13/372,426
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`Page 9
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`Art Unit: 1649
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`the advisory action.
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`In no event, however, will the statutory period for reply expire later
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`than SIX MONTHS from the mailing date of this final action.
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`Any inquiry concerning this communication or earlier communications from the
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`examiner should be directed to JOHN ULM whose telephone number is (571 )272—0880.
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`The examiner can normally be reached on 9:00AM to 5:30PM.
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`If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
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`supervisor, Jeffrey Stucker can be reached on (571) 272-0911. The fax phone number
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`for the organization where this application or proceeding is assigned is 571 -273-8300.
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`Information regarding the status of an application may be obtained from the
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`Patent Application Information Retrieval (PAIR) system. Status information for
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`published applications may be obtained from either Private PAIR or Public PAIR.
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`Status information for unpublished applications is available through Private PAIR only.
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`For more information about the PAIR system, see http://pair-direct.uspto.gov. Should
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`you have questions on access to the Private PAIR system, contact the Electronic
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`Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a
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`USPTO Customer Service Representative or access to the automated information
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`system, call 800-786-9199 (IN USA OR CANADA) or 571-272—1000.
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`/John D. Ulm/
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`Primary Examiner, Art Unit 1649
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`Application/Control Number: 13/372,426
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`Art Unit: 1649
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