UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 2231371450
`www.uspto.gov
`
`15/023,165
`
`03/18/2016
`
`Alex Loukas
`
`FAK-10202/47
`
`7025
`
`759°
`”006
`DINSMORE & SHOHL LLP
`
`01/23/2019
`
`900 Wilshire Drive
`Suite 300
`mm 14148084
`
`MIKNIS' ZACHARY J
`
`1654
`
`MW
`
`NOTIFICATION DATE
`
`DELIVERY MODE
`
`01/23/2019
`
`ELECTRONIC
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`Notice of the Office communication was sent electronically on above—indicated "Notification Date" to the
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`following e—mail address(es):
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`MiehiganPatTM@dinsmore.eom
`
`PTOL-90A (Rev. 04/07)
`
`

`

`Off/09 A0170” Summary
`
`Application No.
`15/023,165
`Examiner
`ZACHARY J MIKNIS
`
`Applicant(s)
`Loukas et al.
`Art Unit
`1654
`
`AIA Status
`Yes
`
`- The MAILING DA TE of this communication appears on the cover sheet wit/7 the correspondence address -
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE g MONTHS FROM THE MAILING
`DATE OF THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR 1.136(a). In no event, however, may a reply be timely filed after SIX (6) MONTHS from the mailing
`date of this communication.
`|f 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).
`
`Status
`
`1). Responsive to communication(s) filed on 12 October 2018.
`[:1 A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/were filed on
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`2a). This action is FINAL.
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`2b) C] This action is non-final.
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`3)[:] An election was made by the applicant in response to a restriction requirement set forth during the interview on
`; 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
`closed in accordance with the practice under Expat/7e Quay/e, 1935 CD. 11, 453 O.G. 213.
`
`Disposition of Claims*
`5)
`Claim(s)
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`1—3,5,8—10,14—16,18—28,31—42 and 45—48 is/are pending in the application.
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`5a) Of the above claim(s) 1—3,5,14—16,18—28,31—33 and 41—42 is/are withdrawn from consideration.
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`E] Claim(s)
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`is/are allowed.
`
`Claim(s) 8—10,34—40,45 and 47 is/are rejected.
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`Claim(s) 46 and 48 is/are objected to.
`
`) ) ) )
`
`
`
`are subject to restriction and/or election requirement
`E] Claim(s)
`* If any claims have been determined aflowabie. 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
`
`httpfiwww.usptogovlpatentslinit_events[pph[index.'§p or send an inquiry to PPeredhagk@usptg.ggv.
`
`Application Papers
`
`10)D The specification is objected to by the Examiner.
`
`11). The drawing(s) filed on 18 March 2016 is/are: a). accepted or b)[j 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).
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121 (d).
`
`Priority under 35 U.S.C. § 119
`12). Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`Certified copies:
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`a). All
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`b)l:] Some”
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`c)l:I None of the:
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`1.8 Certified copies of the priority documents have been received.
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`2.8 Certified copies of the priority documents have been received in Application No.
`
`3.. Copies of the certified copies of the priority documents have been received in this National Stage
`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.
`
`Attachment(s)
`
`1)
`
`Notice of References Cited (PTO-892)
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`Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`2)
`Paper No(s)/Mail Date_
`U.S. Patent and Trademark Office
`
`3) C] Interview Summary (PTO-413)
`Paper No(s)/Mail Date
`4) CI Other-
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`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`Part of Paper No./Mai| Date 20190117
`
`

`

`Application/Control Number: 15/023,165
`Art Unit: 1654
`
`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, filed on or after March 16, 2013, is being examined
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`under the first inventor to file provisions of the AIA.
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`Claim Status
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`Claims 4, 6, 7, 11-13, 17, 29, 30, 43, and 44 have been canceled. Claims 1-3, 5,
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`8-10, 14-16, 18-28, 31-42, and 45-48 are pending. Claims 1-3, 5, 14-16, 18-28, 31-33,
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`41, and 42 are withdrawn with traverse. Claims 8-10, 34-40, and 45-48 are being
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`examined on the merits.
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`Election/Restrictions
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`Applicant's election with traverse of Group II (claims 8-10 and 34-40) in the reply
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`filed on 15 November 2016 is acknowledged. The traversal is on the ground(s) that the
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`‘822 application as cited to break unity of invention is commonly owned, and thus not
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`prior art. This is not found persuasive because even allowing for the ‘822 application to
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`be disqualified as prior art under 35 U.S.C. 102(b)(2) owing to the common ownership
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`statement as filed, the special technical feature (a modified Ac—TMP-2 protein) is still
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`known as found in the rejection presented below under 35 U.S.C. 103.
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`The requirement is still deemed proper and is therefore made FINAL.
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`Claims 1-3, 5, 14-16, 18-28, 31-33, 41, and 42 are withdrawn from further
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`consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention,
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 3
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`there being no allowable generic or linking claim. Applicant timely traversed the
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`restriction (election) requirement in the reply filed on 15 November 2016.
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`I. Modified Rejections:
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`Claim Rejections - 35 USC § 103
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`In the event the determination of the status of the application as subject to NA 35
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`U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any
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`correction of the statutory basis for the rejection will not be considered a new ground of
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`rejection if the prior art relied upon, and the rationale supporting the rejection, would be
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`the same under either status.
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`This application currently names joint inventors. In considering patentability of the
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`claims the examiner presumes that the subject matter of the various claims was
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`commonly owned as of the effective filing date of the claimed invention(s) absent any
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`evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to
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`point out the inventor and effective filing dates of each claim that was not commonly
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`owned as of the effective filing date of the later invention in order for the examiner to
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`consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2)
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`prior art against the later invention.
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`The following is a quotation of 35 U.S.C. 103 which forms the basis for all
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`obviousness rejections set forth in this Office action:
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`A patent for a claimed invention may not be obtained, notwithstanding that the claimed
`invention is not identically disclosed as set forth in section 102, if the differences between the
`claimed invention and the prior art are such that the claimed invention as a whole would have
`been obvious before the effective filing date of the claimed invention to a person having
`ordinary skill in the art to which the claimed invention pertains. Patentability shall not be
`negated by the manner in which the invention was made.
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
`
`Page 4
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`The factual inquiries set forth in Graham v. John Deere Co., 383 US. 1, 148
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`USPQ 459 (1966), that are applied for establishing a background for determining
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`obviousness under 35 U.S.C. 103 are summarized as follows:
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`1. Determining the scope and contents of the prior art.
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`2. Ascertaining the differences between the prior art and the claims at issue.
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`3. Resolving the level of ordinary skill in the pertinent art.
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`4. Considering objective evidence present in the application indicating
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`obviousness or nonobviousness.
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`1. Claims 8 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over
`
`Zhan et al. (Mol. & Biochem. Parasitology 162:142-148, published 2008, hereafter
`
`referred to as Zhan).
`
`The Zhan art teaches the cloning of Ac—TMP-2 (see e.g. Abstract). Zhan teaches
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`that the protein is 244 amino acids in length, and contains a N-terminal 16 amino acid-
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`long signal sequence that is cleaved between Ala16 and Ala17 of full-length Ac—TMP-2
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`(see e.g. Section 3.1, Figure 1). An N-linked glycosylation site is taught at position 64
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`(see e.g. Section 3.1). The recombinant Ac—TMP-2 peptide of Zhan is taught to inhibit
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`MMP-13, MMP-7, and MMP-2 strongly (see e.g. Figure 5 and Section 3.5). The Ac-
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`TMP-2 peptide is taught to contain the canonical C-X-C sequence found in other
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`nematode TlMPs (see e.g. Section 4). In discussing the strong inhibition of MMP-2,
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`MMP-7, and MMP-13 by Ac—TMP-2, Zhan teaches that MMPs play roles in modulating
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`host inflammatory reactions (see e.g. p.147 Col.1 112). In particular, Zhan suggests that
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`hookworms secrete Ac—TMP-2 to inhibit proinflammatory MMPs to down-regulate host
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`immune responses (see e.g. p.147 Col.1 112).
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 5
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`The difference between Zhan and the claimed invention is that Zhan does not
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`explicitly teach removal of the secretion signal or N-linked glycosylation site from Ac-
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`TMP-2, nor does Zhan explicitly teach that Ac—TMP-2 is capable of reducing and/or
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`alleviating inflammation upon administration to a subject in need thereof.
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`It would be obvious to one of ordinary skill in the art before the effective filing
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`date of the claimed invention from the teachings of Zhan regarding the signal sequence
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`that a recombinant protein should be prepared by removing said signal sequence amino
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`acids from the N-terminus. It would also be obvious to remove the N-linked
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`glycosylation site to reduce heterogeneity in expressed protein by mutating the Asn to a
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`Gin that cannot be glycosylated and is structurally similar to Asn (as is known for other
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`tissue inhibitors of metalloproteinases, see e.g. Caterina et al. Biochim. Biophys. Acta
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`14:21 -34, published 14 October 1998). The resulting peptide at a minimum comprises
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`SEQ ID NO:4 as it lacks the N-terminal secretion signal and has a removal of the N-
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`linked glycosylation site by an N640 mutation. Furthermore, given the teachings that
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`Ac—TMP-2 inhibits MMP-2, MMP-7, and MMP-13 and the knowledge in the art that each
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`are involved in pro-inflammatory responses, one of ordinary skill would find it obvious to
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`apply Ac—TMP-2 to reduce inflammation in a subject in need thereof. This is especially
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`true given that Zhan explicitly suggests that hookworms utilize Ac—TMP-2 for this exact
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`purpose in order to evade immune system detection. The Zhan art provides specific
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`motivation to remove the signal sequence since it is not a functional part of the peptide,
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`and provides a strong suggestion that Ac—TMP-2 can be utilized as an anti-inflammatory
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`modulator. The teachings of the peptide and usefulness in Zhan provide a reasonable
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`expectation that application to a patient suffering from inflammation would be successful
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 6
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`in reducing inflammation, especially given the inhibition of the various MMP functions by
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`Ac—TMP-2. The invention would be prima facie obvious to one of ordinary skill in the art
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`before the effective filing date of the claimed invention.
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`With respect to claim 47, removal of the N-terminal signal peptide and mutation
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`of the Asn64 to Gin leads to an Ac—TMP-2 consisting of SEQ ID NO:4.
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`Response to Arguments:
`
`The Applicants argue that Zhan does not teaches or suggest an Ac-TMP-2
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`lacking one or more C-terminal amino acids is capable of reducing and/or alleviating
`
`inflammation or that this property would be expected in a modified protein.
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`The Examiner agrees that Zhan does not teach an Ac-TMP-2 protein having a
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`truncated C-terminus. However, the claims do not require that the Ac-TMP-2 to be
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`limited to only those with a truncated C-terminus. Claim 8 recites that the administration
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`is of “a modified Ac-TMP-2 protein, wherein the modified Ac-TMP-2 protein comprises:
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`(i) an amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:5, or (ii) an amino
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`acid sequence set forth in SEQ ID NO:1 which lacks one or a plurality of C-terminal
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`amino acids normally present in a full length or wild-type Ac-TMP-2 protein...”
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`(emphasis added). It is clear from claim 8 that one of the options is that the modified Ac-
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`TMP-2 protein can be SEQ ID NO:4 or 5. The Examiner argues that as presented
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`supra, the Zhan art provides for the modified Ac-TMP-2 of SEQ ID NO:4 by (1) removal
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`of the N-terminal signal sequence and (2) removal of the N-terminal glycosylation
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`residue. Nothing in claim 8 requires that there be C-terminal deletions in any modified
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`Ac-TMP-2 protein, only that this is an option for a modified Ac-TMP-2 protein. As to the
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`reduction or alleviation of inflammation, as the Examiner has set forth the Ac-TMP-2
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 7
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`protein is already known to inhibit MMPs involved in pro-inflammatory processes, such
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`that it would be reasonably expected that inhibition of those MMPs would also result in
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`an reduction or alleviation of inflammation in a subject by inhibiting those inflammatory
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`pathways.
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`The Applicants argue claim 8 has been amended to comprise the Ac-TMP-2
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`proteins as being SEQ ID NO:4 or 5, or a C-terminal deletion of wild-type sequences to
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`arrive at SEQ ID NO:1.
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`The Examiner agrees that the claim has been amended to limit the Ac-TMP-2
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`protein. The Examiner argues that Zhan still provides for SEQ ID NO:4 as claimed, i.e.
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`one where the N-terminal signal sequence is removed and the glycosylation site
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`removed by standard mutagenesis techniques known to be utilized in other tissue
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`inhibitors of metalloproteinases.
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`The Applicants argue the N48Q mutation is not taught in Zhan for SEQ ID NOs:4
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`or 5.
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`The Examiner argues that Zhan highlights that N48 is a site for glycosylation.
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`The Examiner further argues that it is known that removal of glycosylation sites can
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`provide for better homogeneity in a recombinantly produced protein, as it is generally
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`known that glycosylation is heterogeneous (see e.g. An et al. Curr. Opin. Chem. Biol.
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`13:421-426, published October 2009, in particular Introduction). This combined with the
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`knowledge that removal of N-Iinked glycosylation sites in related tissue inhibitors of
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`metalloproteinases was generally accepted leads to one of ordinary skill in the art
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`seeking to remove the glycosylation site by known mutagenesis of Asn to a structurally
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`similar but non-modifiable Gin residue.
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 8
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`The Applicants argue with regards to SEQ ID NO:1 that Zhan describes an
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`immunomodulatory role for Ac-TMP-2 that is different from the general anti-
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`inflammatory role. The Applicants argue Zhan proposes Ac-TMP-2 be administered for
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`provoking an immune response, and describes it as an immune-dominant protein of
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`hookworms. The Applicants argue immunodominance means that it elicits an immune
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`response larger in magnitude and/or more frequent than other molecules. The
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`Applicants argue Zhan teaches away from using it as an anti-inflammatory by stating
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`that is being studied as a vaccine candidate. The Applicants argue the goal of Zhan is
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`immune system stimulation that is opposite of being anti-inflammatory.
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`The Examiner argues that he has addressed the arguments concerning the
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`supposed immunomodulatory role of Ac-TMP-2 in Zhan as compared to the claimed
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`anti-inflammatory role in the previous Action. The Zhan art explicitly discusses
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`modulation of MMPs as a way of altering host inflammatory reactions (see e.g. p.147
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`001.1 112). The Zhan art also discusses secretion of Ac-TMP-2 to inhibit proinflammatory
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`MMPs (see e.g. p.147 001.1 112). The skilled artisan can reasonably infer from these
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`teachings, as well as the inhibition of specific MMPs involved in inflammation, that the
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`activity of Ac-TMP-2 is to act as an anti-inflammatory mediator. The artisan has a high
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`level of skill and could easily infer from Zhan the anti-inflammatory activity. "A person of
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`ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSFi’
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`lnt'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[|]n many
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`cases a person of ordinary skill will be able to fit the teachings of multiple patents
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`together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may
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`also take into account "the inferences and creative steps that a person of ordinary skill
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 9
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`in the art would employ." Id. at 418, 82 USPQZd at 1396. In this case the artisan can put
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`together the pieces of the puzzle left within Zhan pertaining to direct MMP inhibition and
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`Ac-TMP-2 action as an inhibitor of pro-inflammatory mediators when secreted. While
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`Zhan might describe immune responses and describe Ac-TMP-2 as an immune-
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`dominant protein, it still describes modulation of proteins in the inflammatory pathway.
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`Again, it is within the level of ordinary skill in the art to apply the inhibition of
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`inflammatory pathway proteins to inhibition of inflammatory activity in line with KSFi’.
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`Even acknowledging that Ac-TMP-2 might be an immunodominant protein, the
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`Examiner argues that does not dissuade from use in an anti-inflammatory role given
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`Zhan’s teaching inhibiting pro-inflammatory MMP release. The artisan can still use such
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`teachings to lead to anti-inflammatory rather than a vaccine-only role.
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`The Applicants argue Zhan teaches formulation with an adjuvant for vaccine
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`development. The Applicants argue this leads to Zhan only providing for enhancement
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`of immune-stimulating activities of Ac-TMP-2 rather than ant-inflammatory activity as
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`claimed.
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`Again, the Examiner argues that while Zhan might teach use in a vaccine
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`application, including a further adjuvant, this does not dissuade the skilled artisan from
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`using Ac-TMP-2 in an anti-inflammatory role. Zhan specifically provides for inhibition of
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`proinflammatory MMPs: “It is possible that hookworms secrete Ac-TMP-2 to inhibit
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`proinflammatory MMPs as a basis for host immunomodulation” (see e.g. p.147,
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`emphasis added). Additionally, Zhan teaches that “Ac-TMP-2 inhibits the human matrix
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`metalloproteinases, MMP-2, MMP-7, and MMP-13” (see e.g. p.147), again which are
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`involved in pro-inflammatory processes. 80 while Ac-TMP-2 might be useful in an
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 10
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`immunomodulatory role, Zhan provides a reasonable teaching that the basis of that
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`immunomodulatory role is by an anti-inflammatory effect by inhibiting pro-inflammatory
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`MMPs. The immunomodulation results from the anti-inflammatory role.
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`The Applicants again argue Zhan provides no motivation to provide SEQ ID NO:4
`
`or 5, nor a C-terminal deletion as in SEQ ID NOs:1 or 5.
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`The Examiner disagrees for the same reasons set forth supra.
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`The rejection is modified and maintained.
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`2. Claims 9, 10, 34-37, 40, and 45 are rejected under 35 U.S.C. 103 as being
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`unpatentable over Zhan et al. (Moi. & Biochem. Parasitology 162:142—148, published
`
`2008) as applied to claim 8 above, and further in view of Tremain WJ (Neth. J. Med.
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`50:812-4, published 1997, hereafter referred to as Tremain).
`
`The relevance of Zhan is set forth supra. The difference between Zhan and the
`
`claimed invention is that Zhan does not specifically teach that the inflammation is
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`associated with any sort of disease or disorder, nor that the disease or disorder is
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`refractory to baseline treatment. Additionally, Zhan does not teach the diseases in
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`claims 34-37 or additional treatment in claim 40.
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`Tremaine teaches that refractory IBS is a persistent acute disease despite anti-
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`inflammatoryinterventions (see e.g. Abstract). Tremaine teaches that azathiprine, 6-
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`mercaptopurine, methotrexate, cyclosporine, and experimental strategies are treatment
`
`options, and that 6-mercaptopurine is effective in ~75% of Crohn's disease patients (see
`
`e.g. Abstract). Tremaine also teaches cyclosporine may be useful for severe ulcerative
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`colitis (see e.g. Abstract).
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
`
`Page 11
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`It would be obvious to one of ordinary skill in the art before the effective filing
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`date of the claimed invention that in the case of refractory IBS, including Crohn's
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`disease and severe ulcerative colitis, that the anti-inflammatory Ac—TMP-2 of Zhan could
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`serve as a potential anti-inflammatory modulator as compared to the baseline
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`treatments that prove to be ineffective. The motivation to seek other anti-inflammatory
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`compounds comes from the teachings in Tremaine that current anti-inflammatory
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`treatments can prove ineffective, motivating one of ordinary skill to seek other anti-
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`inflammatory modulators for use in treatment. Given that Zhan establishes such activity
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`is found in Ac—TMP-2, one of ordinary skill would reasonably seek to utilize it in
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`treatment of refractory IBS. Since Ac—TMP-2 possesses anti-inflammatory activity and is
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`not a baseline therapy already utilized for treatment of IBS, one of ordinary skill would
`
`expect it to provide a measure of inflammatory relief in IBS patients. The invention
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`would be prima facie obvious to one of ordinary skill in the art before the effective filing
`
`date of the claimed invention.
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`With respect to claim 9, the administration of Ac—TMP-2 to generally treat
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`inflammation by inhibiting MMP pathways would result in treatment of the inflammation,
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`regardless of how the inflammation arises. In this case, the inflammation would be
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`associated with IBS (a known feature of IBS), and one of ordinary skill would expect the
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`inflammation to be treated via inhibition of the MMP pathways by Ac—TMP-2.
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`With respect to claim 10, Tremaine sets forth already that the IBS is refractory to
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`baseline treatment with known anti-inflammatory compounds.
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`With respect to claims 34-37, the refractory IBS, Crohn’s disease, and ulcerative
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`colitis of Tremaine read upon the genera and species as claimed.
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`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 12
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`With respect to claims 40 and 45, the Tremaine art sets forth several other
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`therapies that are useful for Crohn’s and ulcerative colitis patients in at least certain
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`situations, including cyclosporine (an immunosuppressant). It would be obvious that
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`said treatments should be combined with the anti-inflammatory treatment of Zhan in
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`order to treat the Crohn's/UC on multiple levels, especially with the expectation that
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`additive treatment would be more effective than treatment with a single compound.
`
`Response to Arguments:
`
`The Applicants argue Tremaine does not cure the deficiencies of Zhan. The
`
`Applicants argue since Zhan is overcome by the arguments presented supra there is no
`
`reason to conclude that one of ordinary skill in the art would combine Zhan and
`
`Tremaine for alleviation of inflammation associated with a disease of the digestive tract.
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`The Examiner has addressed the arguments against Zhan supra and does not
`
`find them persuasive. As no additional arguments are provided on the merits of
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`Tremaine, the arguments are unpersuasive.
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`The rejection is maintained.
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`3. Claims 9, 38, and 39 are rejected under 35 U.S.C. 103 as being unpatentable
`
`over Zhan et al. (Moi. & Biochem. Parasitology 162:142-148, published 2008) as
`
`applied to claim 8 above, and further in view of Cazzola et al. (Eur. Resp. J. 40:724-
`
`741, published 10 April 2012, hereafter referred to as Cazzola)
`
`The relevance of Zhan is set forth supra. The difference between Zhan and the
`
`claimed invention is that Zhan does not teach that the disease associated with
`
`

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`Application/Control Number: 15/023,165
`Art Unit: 1654
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`Page 13
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`inflammation is a respiratory disease, including asthma, emphysema, chronic bronchitis,
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`or COPD.
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`Cazzola teaches that a hallmark of COPD is inflammation in the lungs (see e.g.
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`p.724 Golf 111). Cazzola teaches that anti-inflammatory needs of COPD patients are
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`not met (see e.g. p.724 Golf 112 to Col.2 111). Statins are discussed as an anti-
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`inflammatory agent of interest, and it is noted that they reduce production of MMPs, in
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`particular MMP-1, MMP-2, and MMP-9 (see e.g. p.734 Col.2 114).
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`It would be obvious to one of ordinary skill in the art before the effective filing
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`date of the claimed invention to utilize the anti-inflammatory Ac—TMP-2 as taught in
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`Zhan for treatment of COPD as taught in Cazzola by focusing on inflammation present
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`in COPD patients. The motivation to utilize Ac—TMP-2 comes from the Cazzola art,
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`which teaches the concept of utilizing a wide variety of anti-inflammatory modulators as
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`well as focusing on those that modulate MMP production. Given that Ac—TMP-2 acts on
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`MMPs, it would be reasonable to utilize them for treatment of COPD. Given that the Ac-
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`TMP-2 was known to be anti-inflammatory, one of ordinary skill in the art would also
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`expect it to influence inflammation in COPD by acting on MMP pathways. The invention
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`would be prima facie obvious to one of ordinary skill in the art before the effective filing
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`date of the claimed invention.
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`With respect to claim 9, Cazzola as set forth supra establishes that inflammation
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`is associated with COPD.
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`With respect to claims 38 and 39, COPD as taught in Cazzola is a species as
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`recited from the genus of respiratory system diseases.
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`Response to Arguments:
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`

`

`Application/Control Number: 15/023,165
`Art Unit: 1654
`
`Page 14
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`The Applicants argue Cazzola does not cure the deficiencies of Zhan. The
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`Applicants argue since Zhan is overcome by the arguments presented supra there is no
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`reason to conclude that one of ordinary skill in the art would combine Zhan and
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`Tremaine for alleviation of inflammation associated with a disease of the respiratory
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`system.
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`The Examiner has addressed the arguments against Zhan supra and does not
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`find them persuasive. As no additional arguments are provided on the merits of
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`Cazzola, the arguments are unpersuasive.
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`The rejection is maintained.
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`Double Parenting
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`The nonstatutory double patenting rejection is based on a judicially created
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`doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the
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`unjustified or improper timewise extension of the “right to exclude” granted by a patent
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`and to prevent possible harassment by multiple assignees. A nonstatutory double
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`patenting rejection is appropriate where the conflicting claims are not identical, but at
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`least one examined application claim is not patentably distinct from the reference
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`claim(s) because the examined application claim is either anticipated by, or would have
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`been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46
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`USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed.
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`Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum,
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`686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619
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`(CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
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`

`

`Application/Control Number: 15/023,165
`Art Unit: 1654
`
`Page 15
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`A timely filed terminal disclaimer in compliance with 37 CFR 1.321 (c) or 1.321 (d)
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`may be used to overcome an actual or provisional rejection based on nonstatutory
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`double patenting provided the reference application or patent either is shown to be
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`commonly owned with the examined application, or claims an invention made as a
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`result of activities undertaken within the scope of a joint research agreement. See
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`MPEP § 717.02 for applications subject to examination under the first inventor to file
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`provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) -
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`706.02(l)(3) for applications not subject to examination under the first inventor to file
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`provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR
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`1.321 (b).
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`The USPTO Internet website contains terminal disclaimer forms which may be
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`used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application
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`in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26,
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`PTO/AlA/25, or PTO/AlA/26) should be used. A web-based eTerminal Disclaimer may
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`be filled out completely online using web-screens. An eTerminal Disclaimer that meets
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`all requirements is auto-processed and approved immediately upon submission. For
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`more information about eTerminal Disclaimers, refer to
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`www.uspto.gov/patents/process/file/efs/guidance/eTD-info-l.jsp.
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`Claims 8-10, 34-40, 45, and 47 are rejected on the ground of nonstatutory
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`double patenting as being unpatentable over claims 1-3, 11-15, and 19 of U.S. Patent
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`No. 9,637,527 in view of Zhan et al. (Moi. & Biochem. Parasitology 162:142-148,
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`published 2008). Although the claims at issue are not identical, they are not patentably
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`distinct from each other because the ‘527 patent claims methods of treatment using full-
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`

`

`Application/Control Number: 15/023,165
`Art Unit: 1654
`
`Page 16
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`length Ac—TMP-2, which can reasonably be substituted by the mature peptide of Zhan
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`and read upon the instant claims.
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`The ‘527 patent claims a method of treating inflammation using a peptide of SEQ
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`ID NO:2 (see e.g. claim 1), which is full-length Ac—TMP-2 containing a secretion signal.
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`The difference between '527 and the claimed invention is that '527 does not claim use
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`of a modified Ac—TMP-2 protein comprising SEQ ID NO:4.
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`The relevance of Zhan has been set forth supra. As argued, the Zhan art
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`reasonably makes obvious production of mature Ac—TMP-2 lacking the N-terminal signal
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`sequence as well as removal of the N-linked glycosylation site (a N64Q mutation) in
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`light of the prior art to arrive at SEQ ID NO:4.
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`It would be obvious to one of ordinary skill in the art before the effective filing
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`date of the claimed invention to substitute the Ac—TMP-2 of Zhan for the wild-type full-
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`length protein as claimed in '527. The motivation to substitute comes from the fact that
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`both proteins are relatives to one another. Since highly similar compounds are being
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`utilized, one of ordinary skill would expect the same anti-inflammatory properties to be
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`maintained, especially given that Zhan teaches similar effects. The invention would be
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`prima facie obvious to one of ordinary skill in the art before the effective filing date of the
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`claimed invention.
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`With respect to claims 9 and 10, the ‘527 patent claims the same source of
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`inflammation and refractory response to baseline therapies (see e.g. claims 2 and 3).
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`With respect to claims 34-37, the ‘527 patent claims the same diseases of the
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`digestive tract, including Crohn’s and ulcerative colitis (see e.g. claims 11-13).
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`

`

`Application/Control Number: 15/023,165
`Art Unit: 1654
`
`Page 17
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`With respect to claims 38 and 39, the ‘527 patent claims the same respiratory
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`diseases, including asthma, emphysema, chronic bronchitis, and COPD (see e.g.
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`claims 14 and 15).
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`With respect to claim 40, the ‘527 patent claims further administration of an
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`additional agent, including the same genera as instantly claimed (see e.g. claim 19).
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`With respect to claim 43, the ‘527 patent in light of Zhan results in a peptide with
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`at least 95% identity to SEQ ID NO:1 or SEQ ID NO:4.
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`With respect to claim 44, the ‘527 patent in light of Zhan provides a N-terminal C-
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`X-C motif.
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`With respect to claim 45, the ‘527 patent claims further administration of an
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`additional agent, including the same genera as instantly claimed (see e.g. claim 19).
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`Response to Arguments:
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`The Applicants argue that appropriate action will be taken at allowance. The
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`Applicants' arguments have been considered but are not persuasive.
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`The proper response to the double patenting rejection is via filing of a terminal
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`disclaimer over the ‘527 patent, arguments establishing why the '527 patent in view of
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`Zhan is not obvious,