UNITED STATES PATENT AND TRADEMARK OFFICE
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`l'NlTED STATES DEPARTMENT OF COMMERCE
`l'nlled States Patent and Trademark (Mlle:-
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`Address' %g\r§hlll:2’0\bk FOR l’A'l'EN'lS
`Aleumllu. Virginia JI‘I ‘vl-lfill
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`(‘()Nl'lRM.o\'l'l()N NO.
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`I'IRS'l' NAMED lNVlle‘OR
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`APPLK'AHON NO.
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`”$55,168
`09/15/10l5
`Slcphen Ruddy
`SHR- l 20-" IS
`8700
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`IIJ'l/lZ/Z'Jlfi
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`1‘30?7§
`Shire Human (icnctlcs lhcrapics, Inc.
`c/o l’rosknucr Rose LLI’
`()ne lnlemalional Place
`B MA 02110
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`EXAMINER
`MIKNIST ZACHARY J
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`1075
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`NOUFR'ZATION DATE
`DEIil\"l".RY MODE
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`(l7/l2f20l6
`lilJi("l'R0l\'l(‘
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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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`Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
`following e-mail addness(es):
`dockelingpatemboston @proskauer.c0m
`oandrcws @proskaucr.com
`shircip @Shirccom
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`P'lOL-OOA (Rev. 04/07)
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`Page 1 of 18
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`CSL EXHIBIT 1076
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`Applicant(s)
`Application No.
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` 14/855,168 RUDDY ET AL.
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`AIA (First Inventor to File)
`Examiner
`Art Unit
`Office Action Summary
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`1675ZACHAFIY J. MIKNIS Sthtus
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`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address --
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`Period for Reply
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE Q MONTHS FROM THE MAILING DATE OF
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`THIS COMMUNICATION.
`In no event, however may a reply be timely filed
`Extensions oftime may be available under the provisions of 37 CFR 1.136(a).
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`after SIX (6) MONTHS from the mailing date of thIs communication.
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`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date ofthis communication.
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`- 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).
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`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
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`earned patent term adjustment. See 37 CFR 1.704(b).
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` Attachment(s)
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`Status
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`1)IZI Responsive to communication(s) filed on 23 November 2015.
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`El A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on
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`2a)E| This action is FINAL.
`2b)|:| This action is non-final.
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`3)l:| 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)|:| 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 QC. 213.
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`Disposition of Claims*
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`5)IZI Claim(s) 16 18 20 21 32—35 and 46—53 is/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 El Claim 3)
`is/are allowed.
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`) 16 18 20 21 32-35 and 46-53 is/are rejected
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`)_ is/are objected to.
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`9)|:I Claim(s)
`are subject to restriction and/or election requirement.
`* If any claims have been determined allowable, you may be eligible to benefit from the Patent Prosecution Highway program at a
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`participating intellectual property office for the corresponding application. For more information. please see
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`I/r’\NVIiW,LJSDiO.CiO\// atents/init events/ .
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`/’index.’s or send an inquiry to Pl-‘l—iteedbackftbusptocbv.
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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)|Z The drawing(s) filed on 23 March 2016 is/are: a)IZ accepted or b)l:l objected to by the Examiner.
`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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`Priority under 35 U.S.C. § 119
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`12)I:l Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
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`Certified copies:
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`a)I:I All
`b)l:l Some“ c)I:I None of the:
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`1.|:I Certified copies of the priority documents have been received.
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`2.|:I Certified copies of the priority documents have been received in Application No.
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`3.I: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)).
`** See the attached detailed Office action for a list of the certified copies not received.
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`1) E Notice of References Cited (PTO-892)
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`2) IX Information Disclosure Statement(s) (PTO/SB/OSa and/or PTO/SB/OSb)
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`Paper No(s)/Mai| Date
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`U 8 Patent and Trademark Office
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`PTOL—326 (Rev. 11-18)
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`3) I] Interview Summary 0:10.413)
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`Paper No(s)/Mai| Date.
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`4 l:l O h
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`Office Action Summary
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`Part of Paper No./Mai| Date 20160629
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`Page 2 of 18
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`Page 2 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 2
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`DETAILED ACTION
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`Notice of Pre-AIA or AIA Status
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`The present application is being examined under the pre-AIA first to invent
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`provisions.
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`Claim Status
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`Claims 1-15, 17, 19, 22-31 and 36-45 have been canceled. Claims 16, 18, 20,
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`21, 32-35, and 46-53 are pending and are being examined on the merits.
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`Election/Restrictions
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`Applicant’s election without traverse of Group | (claims 16-35) in the reply filed on
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`23 November 2015 is acknowledged.
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`Claims 36-45 (drawn to Group II) have been canceled by the Applicant prior to
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`allowance. Per MPEP 821 .O4(b), the restriction is maintained and made FINAL in order
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`to preserve Applicant’s rights under 35 U.S.C. 121 with respect to double patenting.
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`Declarations Under 37 C.F.R. 1. 132
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`1. The Declaration of Michael Frank is found to be sufficient to establish that the
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`Jiang art is not anticipatory, demonstrating that it featured administration of Cinryze at
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`100 U/mL, not the at least 400 U/mL as now claimed. Additionally, the Frank
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 3
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`Declaration establishes the total volume of the injection (8 to 11.5 mL) and timing (30 to
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`2. The Declaration of Jennifer Schranz has been considered and found partially
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`persuasive. The Schranz Declaration is found to establish that the Kreuz art utilized a
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`dosage of 50 U/mL over a larger 10 mL volume and for 15 minutes. The Schranz
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`declaration establishes that Anonymous required hyaluronidase for delivery and was at
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`a dose below that being claimed and at a far higher volume than normally found for
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`subcutaneous delivery.
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`I. New Reiections:
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`Claim Rejections - 35 USC § 103
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`The text of those sections of Title 35, U.S. Code not included in this action can
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`be found in a prior Office action.
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`Claims 16, 18, 20, 21, 32-35, 46, 47, and 49-52 are rejected under pre-AIA 35
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`U.S.C. 103(a) as being unpatentable over Jiang et al. (Clinical Immunology 136:323-
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`328, published 8 June 2010, hereafter referred to as Jiang) and Anonymous (The
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`Pharmaceutics and Compounding Laboratory: Subcutaneous at
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`http://pharmlabs.unc.edu/labs/parenterals/subcutaneous.htm, published 14 June 2010,
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`hereafter referred to as UNC).
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`The Jiang art teaches that Cinryze is approved by the FDA for intravenous
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`administration for prophylactic use in patients with HAE (see e.g. p.323 Col.2 111).
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`It is
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`also taught that HAE patients can have a prodrome period of 1-2 hours, during which
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 4
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`administration of C1 inhibitor can be given to treat acute attacks of HAE (see e.g. p.323
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`Col.2 112 to p.324 Col.1 111). The Jiang art teaches that Cinryze was administered to 16-
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`23 kg pigs at a dosage of 50 U/kg (i.e. 800 to 1150 U in total) intravenously or
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`subcutaneously (see e.g. Materials and Methods, In vivo study design). Infusions given
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`subcutaneously were administered on days 0, 3, and 6 (see e.g. p.325 Col.1 111). The N
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`infusions of Cinryze peaked at 1 hr post-infusion and gradually declined over 3 days,
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`while for subcutaneous administration peak levels were achieved at 6 hrs and were
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`stable over the next three days (see e.g. In vivo protein levels). The Jiang art concludes
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`that subcutaneous administration is a viable treatment option for patients with HAE (see
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`e.g. p.328 Col.1 114).
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`The difference between Jiang and the claimed invention is that Jiang does not
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`teach treatment of patients in need thereof in a specific embodiment, but is fairly
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`suggestive of the claimed method. Additionally, Jiang does not teach the dosage of
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`about 400 U/mL in a single subcutaneous dose.
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`With respect to the dosage of 400 U/ml, one of skill in the art would recognize
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`that a subcutaneous dose of any drug is limited generally to a total injection volume of
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`approximately 2 mL. For instance, see e.g. the previously cited art from UNC. The
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`administered dosage of Cinryze is already known to be 1000 U (for instance, see e.g.
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`FDA Clinical Pharmacology Review from 4 December 2007, in particular p2), and in
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`transfer of drugs from IV administration to subcutaneous administration it is generally
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`still sought to deliver the same dosage. Logically, the conversion of a dose utilized for
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`W. administration to the equivalent total dose for subcutaneous administration would
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 5
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`require the compound itself to be more concentrated, owing to the lower volume of the
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`subcutaneous dose. Other anti-HAE drugs are known for subcutaneous administration
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`(for instance Ecallantide, a 60 amino acid-long peptide) which would provide motivation
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`for other HAE drugs such as Cinryze to be administered subcutaneously, especially
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`given that Cinryze is also a long peptide.
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`It would be obvious to one of ordinary skill in the art at the time of invention that
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`the subcutaneous administration of Cinryze to pigs as taught in Jiang could also be
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`applied to human patients suffering from HAE, given that Jiang teaches that Cinryze is
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`already administered to said patients to treat HAE, albeit intravenously. The teachings
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`of volume limitations of subcutaneous doses would limit the 1000 U of Cinryze to a 2 mL
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`subcutaneous dose, which would have at least 400 U/mL, even considering that Jiang
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`used doses of 100 U/mL (i.e. the artisan would have a motivation from the prior art to
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`make the injection of the entire Cinryze dose limited to a 2 mL volume, resulting in at
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`least 400 U/mL). The resulting increase in blood level would be expected to inherently
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`occur, as the prior art provides for the same method of administration and total volume.
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`The good pharmacokinetics of Cinryze from subcutaneous administration and stable
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`blood profile as compared to lV-administered Cinryze as found in Jiang would suggest
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`to the skilled artisan that subcutaneous administration is desirable over IV
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`administration. The invention could be reproduced with a reasonable expectation of
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`success given that subcutaneous administration is taught by Jiang to be advantageous,
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`Jiang explicitly suggests using said administration to treat human patients with HAE,
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`and the art establishes that a 2 mL dose is a maximum volume for a subcutaneous dose
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`Page 6 of 18
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`Page 6 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 6
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`of a drug (i.e. requiring the Cinryze 1000 U dose to be at a concentration of 500 U/mL).
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`The invention would be prima facie obvious to one of ordinary skill in the art at the time
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`of invention.
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`With respect to claim 18, the dosage in Jiang is already taught in a range that
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`would encompass the dosages as claimed if converted to normal subcutaneous dosage
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`amounts. See above for the teaching that subcutaneous administration is limited to 2
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`mL. A dose of 800U to 1150U would by necessity be limited to 400 U/mL or 575 U/mL if
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`formulated at the maximum 2 mL volume.
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`With respect to claim 20, the Jiang art teaches administration every three days
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`as set forth above.
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`With respect to claim 21, the administration in Jiang is such that it encompasses
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`up to three times a week as claimed (at 0, 3, and 6 days).
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`With respect to claim 32, the Jiang art establishes that blood levels of Cinryze
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`are elevated after subcutaneous administration within 30 minutes, and remain
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`stable/elevated for at least 3 days until the next dosage is administered. One of ordinary
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`skill would expect similar results to occur with a higher dosing regimen required by the 2
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`With respect to claims 33-35, the Jiang art teaches that administration of Cinryze
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`is for treatment and prophylaxis of HAE. HAE only has two isoforms (type | and type II)
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`so by necessity Jiang must be treating those.
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`With respect to claim 46, the known use of Cinryze is for HAE attacks. The same
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`route of administration and method of administration is found in the prior art. By
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`Page 7 of 18
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`Page 7 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 7
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`necessity, it must also result in a decrease in severity and/or number of attacks, as that
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`is the known function of Cinryze. Furthermore, the combined prior art references result
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`in the same dosage and administration route, so the resultant property of the method
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`(decrease in severity and/or number of attacks) must necessarily result.
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`With respect to claim 47, Cinryze is known in the art to be purified from plasma.
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`With respect to claim 49, Cinryze is 100% identical to SEQ ID NO:1.
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`With respect to claim 50, by necessity the preparation of a subcutaneous dose
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`would have to be in the form of a liquid formulation.
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`With respect to claim 51, it is known that Cinryze as used by Jiang is initially
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`supplied as a lyophilized powder that must be reconstituted, as opposed to a pre-made
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`liquid formulation.
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`With respect to claim 52, again since the same method and technique is used to
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`deliver the same protein as claimed, the process would inherently result in the level of
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`the C1 esterase inhibitor in the blood to increase to about 1 U/mL. See MPEP 2112.
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`Response to Arguments:
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`The Applicants argue that Jiang uses a low concentration of 100 U/mL,
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`referencing the Schranz Declaration at 1119. The Applicants also argue that the Frank
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`declaration additionally establishes that the administration of Cinryze was at a dose of
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`100 U/mL. The Applicants argue the low dose would not provide a reasonable
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`expectation of success, and that the clinical trials described by Anonymous and Kreuz
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`demonstrate failure of such a dose. The Applicants argue that the Schranz declaration
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`establishes difficulty in higher concentration of protein drugs. The Applicants argue that
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`Page 8 of 18
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`Page 8 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 8
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`there is high uncertainty as to whether Cinryze could be formulated at a high enough
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`concentration for subcutaneous delivery, arguing that the consensus would be that it
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`could not be formulated as such. The Applicants point out that the field was focused on
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`low concentration formulations which were unsuccessful for subcutaneous
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`administration. The Applicants argue that high volumes (for Anonymous) needed to be
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`administered with a proprietary drug delivery platform based on human hyaluronidase
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`enzyme, which was found not successful due to safety concerns. The Applicants argue
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`that Kreuz showed similar large volumes. The Applicants argue that the invention
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`cannot be obvious in view of the prior art, and discuss the current status of their
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`subcutaneous administration efforts. The Applicants mention "unexpectedly good
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`bioavailability". The Applicants state that a higher administration of Cinryze (1000 U at
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`100 U/mL) achieves 70% bioavailability as compared to a 50 U/mL injection having 40%
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`bioavailability, and argue that this was unexpected because the increased viscosity of
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`the formulation has no impact on absorption and tissue distribution. The Applicants
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`argue that there is a long-felt need for the subcutaneous administration route. The
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`Applicants‘ arguments have been considered but are not persuasive.
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`Firstly, the Examiner agrees with Applicants in that Jiang only teaches a dosage
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`of 100 U/mL. However, as set forth above the general knowledge in the art concerning
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`subcutaneous administration of drugs would motivate one of ordinary skill in the art to
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`modify the dosage regimen of Jiang. Since a normal subcutaneous dose is at most 2
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`mL in volume, one of skill would seek to administer Cinryze at this level or lower, which
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`would by necessity result in an increase in concentration from 100 U/mL to at least 400
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`Page 9 of 18
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`Page 9 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 9
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`U/mL as claimed. The Examiner agrees with the points from both the Schranz and
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`Frank declarations concerning these dosage levels, but cannot ignore what is generally
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`known in the art (volume limits of subcutaneous administration). There is a minor
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`burden to modify the Jiang art in accordance with said known volume levels. There is no
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`evidence that the higher concentration necessarily impacts syringeability or viscosity of
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`the composition. While Cinryze is a large protein,
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`larger 150 kDa proteins are known to
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`be administered subcutaneously without major issues (see e.g. Table 1
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`in World J. Biol.
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`Chem. 26:73-92, published April 2012). The Applicants have provided no actual
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`evidence that the higher concentration posed technical problems beyond
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`assertion/opinion in the remarks and declaration, which is insufficient to establish that
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`the art found this to be a problem.
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`The Applicants are correct in that Anonymous and Kreuz would not provide for
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`the claimed dose. However, the teachings of those pieces of prior art are irrelevant to
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`the above rejection under Jiang and UNC, and the rejections under Anonymous and
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`Kreuz have been withdrawn. As set forth supra, the UNC art provides motivation to seek
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`a total volume of 2 mL or less. This would necessarily result in Jiang being modified to
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`have the Cinryze be at a concentration of at least 400 U/mL. The teachings of
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`Anonymous and Kreuz with respect to the instant rejection are irrelevant since they are
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`not being recited as prior art reading upon the instant claims. Even considering that they
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`might demonstrate later failure of a dose of 100 U/mL, such would motivate one of
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`ordinary skill to seek other dosages, including higher dosages in an effort to ensure that
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`Page 10 of 18
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`Page 10 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 10
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`bioactive Cinryze reaches the bloodstream to act in a prophylactic or therapeutic
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`manner for HAE patients.
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`The Examiner has considered the arguments found in Dr. Schranz’s declaration
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`concerning difficulty in higher concentration formulation. However, Dr. Schranz's
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`declaration provides little more than an assertion that it is difficult to reach such a
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`concentration formulation, as opposed to actual evidence establishing that this (1) was
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`a recognized problem in the art and (2) was generally not achievable via other means.
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`The art cited supra by the Examiner establishes that subcutaneous administration of
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`proteins larger than Cinryze is known in the art (see e.g. the Table 1
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`in the World J. Biol.
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`Chem. Art as cited, particularly Golimumab, Ustekinumab, Enteracept, and Rilonacept).
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`The apparent molecular weight of Cinryze is less than those proteins, which suggests
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`that even considering the extra molecular weight provided by glycosylation, the problem
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`of subcutaneous delivery of large proteins is not insurmountable.
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`Again, as to high concentration formulations, the Applicants have provided no
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`direct evidence that it was considered a problem in the art. The Applicant’s statements
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`to that effect in the Declaration and Remarks are simply assertions not backed up by
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`requisite evidence.
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`As to consideration that the art was focused on low concentration dosages that
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`were found to be insufficient, as set forth supra this would motivate the skilled artisan to
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`seek other dosages. Per KSR, "A person of ordinary skill in the art is also a person of
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`ordinary creativity, not an automaton." KSR Int'l Co. v. Telef/ex Inc., 550 U.S. 398, 421,
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`82 USPQ2d 1385, 1397 (2007). "[l]n many cases a person of ordinary skill will be able
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`Page 11 of 18
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`Page 11 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 11
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`to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82
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`USPQZd 1397. Office personnel may also take into account "the inferences and
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`creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82
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`USPQZd at 1396.”
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`As to the argument that the prior art demonstrates use of a delivery system and
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`high volumes, while this is true, this applies only to the Anonymous art. Jiang makes no
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`mention of the hyaluronidase delivery system. Further, when combined with the
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`required 2 mL injection volume of UNC, the volume is far lower than what is found in
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`either Jiang or Anonymous. The same applies to Kreuz, which is not under
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`consideration or part of the above rejection. While it might utilize higher volumes, the
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`knowledge in the art of a 2 mL subcutaneous dosage motivates one of skill to modify
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`Jiang.
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`The current status of the Applicants’ invention (status in clinical trials) is not
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`found to bear upon the instant rejection in the form of any secondary considerations that
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`would preclude a rejection under 35 U.S.C. 103(a).
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`As to the allegations of unexpected results, firstly as set forth above the art
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`demonstrates that subcutaneous formulations of large proteins (e.g. antibodies) are
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`known. Further, those formulations demonstrate reasonable bioavailability (see e.g.
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`Table 1 of the above World J. Biol. Chem. art). The allegation that the increase in
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`concentration somehow unexpectedly still results in good bioavailability is not
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`persuasive. One of skill would expect that if the dosage of a formulation is doubled, then
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`a roughly double increase in bioavailability should result. Accordingly, the bioavailability
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`Page 12 of 18
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`Page 12 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 12
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`as admitted by the Applicants went from 40% at 50 U/mL to 70% at 100 U/mL. The
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`Examiner does not find any reason why this result is unexpected.
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`Finally, as to the allegations of long felt need, the Examiner has considered the
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`arguments combined with Dr. Schranz’s declaration. Per MPEP 716.04, long felt need
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`must satisfy a three-pronged test:
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`1. The claimed invention must satisfy a long-felt need which was
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`recognized, persistent, and not solved by others.
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`2. The invention must satisfy the long-felt need.
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`3. The evidence must show unsuccessful efforts to solve the problem.
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`The declaration and arguments merely provide assertions to satisfy prong #1.
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`There is no evidence provided that the art generally considered this a long-felt need,
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`which is required to demonstrate that the art a whole considered the lack of a
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`subcutaneous form of administration of a C1 esterase inhibitor to be a long-felt need.
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`The Examiner agrees that the invention is highly useful and beneficial as a
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`subcutaneous dose as compared to the standard intravenous administration route, but
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`this does not in and of itself establish that the art recognized this as a persistent
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`problem not solved by others. For instance, if the art established that previous attempts
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`to high concentration of C1 esterase inhibitors failed due to solubility, syringability, etc.
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`issues, then that might establish evidence of the long felt need not be satisfied by
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`others. The second prong is found by the Examiner to be met by the instantly claimed
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`invention. As to the final prong, there is no clear evidence that high concentration efforts
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`have not been attempted unsuccessfully to solve the problem. As admitted by the
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`Page 13 of 18
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`Page 13 of 18
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`Application/Control Number: 14/855,168
`Art Unit: 1675
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`Page 13
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`Applicants, all other art as cited by the Examiner was concerned with 100 U/mL or lower
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`administration routes. There does not appear to be any evidence that establishes that
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`high concentration subcutaneous administration was identified as a problem and
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`unsuccessfully examined. Again, while the Declaration and arguments make a
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`persuasive case as to why patients suffering from HAE would desire subcutaneous
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`administration routes, neither provides sufficient evidence at this point to successfully
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`establish long-felt need. The long-felt need may be present as alleged, but the
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`arguments as such are right now merely assertions/opinions of a single expert, rather
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`than evidence from the art as a whole that this is truly an art-recognized long felt need.
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`As such, the allegations of long-felt need as a secondary consideration are not found to
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`be sufficient to preclude a rejection under 35 U.S.C. 103(a).
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`The rejection is modified owing to the amendment and maintained.
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