www.uspto.gov
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and TrademarkOffice
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`
`16/982,856
`
`09/21/2020
`
`YONG MIN CHANG
`
`NCIP.P0072US/1001137220
`
`4867
`
`NORTON ROSE FULBRIGHT US LLP
`98 SAN JACINTO BOULEVARD
`SUITE 1100
`
`AUSTIN, TX 78701-4255
`
`SCHLIENTZ, LEAH H
`
`1618
`
`03/17/2023
`
`ELECTRONIC
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`Thetime 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
`following e-mail address(es):
`
`aoipdocket @ nortonrosefulbright.com
`
`PTOL-90A (Rev. 04/07)
`
`

`

`Office Action Summary
`
`Application No.
`16/982,856
`Examiner
`LEAH H SCHLIENTZ
`
`Applicant(s)
`CHANG etal.
`Art Unit
`1618
`
`AIA (FITF) Status
`Yes
`
`-- The MAILING DATEof this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLYIS SET TO EXPIRE 3 MONTHS FROM THE MAILING
`DATE OF THIS COMMUNICATION.
`Extensions of time may be available underthe provisions of 37 CFR 1.136(a). In no event, however, may a reply betimely filed after SIX (6) MONTHSfrom the mailing
`date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHSfrom 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, evenif timely filed, may reduce any earned patent term
`adjustment. See 37 CFR 1.704(b).
`
`Status
`
`
`
`1) Responsive to communication(s) filed on 2/28/2023.
`C} A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/werefiled on
`
`2a)() This action is FINAL. 2b)¥)This action is non-final.
`3)02 An election was madeby the applicant in responseto a restriction requirement set forth during the interview
`on
`; the restriction requirement and election have been incorporated into this action.
`4)\0) 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 Exparte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`Disposition of Claims*
`1-20 and 30-35 is/are pending in the application.
`)
`Claim(s)
`5a) Of the above claim(s)
`is/are withdrawn from consideration.
`Cj} Claim(s)
`is/are allowed.
`Claim(s) 1-20 and 30-35 is/are rejected.
`S)
`) © Claim(s)___is/are objected to.
`Cj) Claim(s
`are subjectto restriction and/or election requirement
`)
`S)
`* If any claims have been determined allowable, you maybeeligible to benefit from the Patent Prosecution Highway program at a
`participating intellectual property office for the corresponding application. For more information, please see
`http://Awww.uspto.gov/patents/init_events/pph/index.jsp or send an inquiry to PPHfeedback@uspto.gov.
`
`) )
`
`Application Papers
`10) The specification is objected to by the Examiner.
`11)0) The drawing(s) filedon__ is/are: a)(J accepted or b)( 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)[VM. Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d)or (f).
`Certified copies:
`c)Z None ofthe:
`b)() Some**
`a) All
`1... Certified copies of the priority documents have been received.
`2.1) Certified copies of the priority documents have beenreceived in Application No.
`3.4% Copies of the certified copies of the priority documents have been receivedin 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)
`
`2) (J Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`Paper No(s)/Mail Date
`U.S. Patent and Trademark Office
`
`3)
`
`(LJ Interview Summary (PTO-413)
`Paper No(s)/Mail Date
`4) (J Other:
`
`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20230309
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 2
`
`DETAILED ACTION
`
`Notice of Pre-AlA or AIA Status
`
`The present application, filed on or after March 16, 2013, is being examined
`
`under the first inventor to file provisions of the AIA.
`
`Continued Examination Under 37 CFR 1.114
`
`A requestfor continued examination under 37 CFR 1.114, including the fee set
`
`forth in 37 CFR 1.17(e), wasfiled in this application after final rejection. Since this
`
`application is eligible for continued examination under 37 CFR 1.114, and the fee set
`
`forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action
`
`has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on
`
`2/28/2023 has been entered.
`
`Status of Claims
`
`Claims 1-10, 12, 14 and 16 have been amended. Claims 1-20 and 30-35 are
`
`pending and are examinedherein on the merits for patentability.
`
`Responseto Arguments
`
`Applicant's arguments have beenfully considered. The rejections have been
`
`modified. The Examiner's response to Applicant’s arguments are incorporated below.
`
`Claim Rejections - 35 USC § 103
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 3
`
`The following is a quotation of 35 U.S.C. 103 which forms the basis for all
`
`obviousnessrejections setforth in this Office action:
`
`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.
`
`The factual inquiries for establishing a background for determining obviousness
`
`under 35 U.S.C. 103 are summarized asfollows:
`
`1. Determining the scope and contents of the prior art.
`
`2. Ascertaining the differences between the prior art and the claims at issue.
`
`3. Resolving the level of ordinary skill in the pertinent art.
`
`4. Considering objective evidence presentin the application indicating
`
`obviousness or nonobviousness.
`
`Claim 1-14, 16-19 and 32-34 are rejected under 35 U.S.C. 103 as being
`
`unpatentable over Port ef a/. (US 2011/0092806)in view of Marnett (US 2005/0002859).
`
`Port teaches the synthesis of a compound (B-Ch) by coupling a biovector to a
`
`linear or macrocyclic chelate; the complexation of the compound (B-Ch) with gallium
`
`Ga68 (paragraph 0024). Various biovectors, linkers and chelates are taught on pages
`
`2-11, including a biovector for targeting a biological target associated with a pathology,
`
`in particular chosen from enzymes (metalloproteases, COX,tyrosine kinase), etc.
`
`Exemplary compounds are shown on pages 50 and 53, including fenobufen and
`
`diflunisal conjugates:
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 4
`
`
`
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`
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`uy
`
`Port does not specifically exemplify a compound according to Formula | as
`
`claimed, including a gadolinium ion and the linker as claimed.
`
`However, DOTA conjugates featuring the claimed linker (CH2CONHCH2CHz2)are
`
`taught to be suitable for conjugation between DOTAandbiovector (e.g. folic acid).
`
` \
`
`SRNRSF FAQSGO at Paed
`
`‘
`
`Further, the teaching is notlimited to gallium, a specific contrast product
`
`vectorized for PET with Ga68 and a contrast product vectorized for MRI with gadolinium
`
`may be used, the biovectors being identical or different (paragraph 0207).
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 5
`
`Marnett teachesa radiological imaging agent by reacting a COX-2-selective
`
`ligand with a compound comprising a detectable group, wherein the COX-2-selective
`
`ligand is a derivative of a non-steroidal anti-inflammatory drug (NSAID) comprising an
`
`ester moiety or a secondary amide moiety (abstract).
`
`The NSAID maybe... sulindac, diflunisal, fenbufen, etc. among others
`
`(paragraph 0035).
`
`The detectable group may be a metal ion chelating group, including DOTA or
`
`DTPA, and binding gadolinium (paragraphs 131).
`
`It would have been obvious to one of ordinary skill in the art at the time of the
`
`invention to substitute the linker between DOTA and the NSAID biovectors exemplified
`
`by Port. While the DOTA-fenbufen and DOTA-diflunisal conjugates do not specifically
`
`recite the claimed linker, Port teaches that a variety of linkers can be used between the
`
`chelate and biovector. One could have readily substituted another exemplified linker, a
`
`(CH2CONHCH2CH2)linker, as a functionally equivalent linker between the chelate and
`
`biovector with a reasonable expectation of successin providing a chelator-linker-
`
`biovector compound for use in imaging.
`
`One could have readily provided an amide bond between a carboxylic acid of the
`
`biovector and an amine of the chelator/linker, analogous to formation of the compound
`
`of page 60 of Port featuring folic acid as a biovector.
`
`5 Ox-OH
`9 Aw
`ok Noes, J H
`Oo
`my LT> a
`NON OS
`N
`-
`HoN@ NN
`
`Folic acid
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 6
`
`Fenbufen, for example, features a similar terminal carboxylic acid to folic acid
`
`available for amide bond formation with a terminal amine of the linker/chelate.
`
`o
`
`O COOH
`
`Further, it would have been obvious to provide a gadolinium ion, as Port teaches
`
`a contrast product vectorized for MRI with gadolinium may be used. Further, Marnett
`
`teachesthe desirability of providing gadolinium chelates (DOTA) as an imaging moiety
`
`in detectable moiety-NSAID conjugate compounds, e.g. for MRI imaging, and teaches
`
`gadolinium to form stable complexes with DOTA.
`
`One would have been further motivated to substitute sulindac as a functionally
`
`equivalent NSAID biovector in view of Marnett, which teaches fenbufen, diflunisal,
`
`sulindac, etc. to be suitable NSAID agents for conjugation to a detectable moiety for use
`
`in imaging.
`
`With regard to claims 8, 9 and 16, it is interpreted that the compounds would
`
`necessarily be capable of coordinating water and achieving the claimed relaxation
`
`properties, as a chemical compound andit’s properties are inseparable. See MPEP
`
`2112.
`
`With regard to claims 7 and 82, it is noted that the recitation of the intended use
`
`of the compound does notdistinguish over the prior art because the intended useof the
`
`claimed invention mustresult in a structural difference between the claimed invention
`
`and the prior art in order to patentably distinguish the claimed invention from the prior
`
`art.
`
`If the prior art structure is capable of performing the intended use, then it meets the
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 7
`
`claim. See /In re Casey, 152 USPQ 235 (CCPA 1967) and /n re Otto, 136 USPQ 458,
`
`459 (CCPA 1963).
`
`With regard to claims 10-14, 30, 33 and 94, it is noted that the only active step in
`
`the claimed method is administration which is performed by Port and Marnett,
`
`accordingly Port and Marnett’s compounds achieve the claimed methodof treating
`
`inflammation or inhibiting a cyclooxygenase-2.
`
`With regard to the limitation “wherein the composition is anti-inflammatory,”
`
`Marnett teaches that sulindac, diflunisal, fenbufen are non-steroidal anti-inflammatory
`
`drugs. Further, a composition and it’s properties are inseparable, see MPEP 2112.
`
`Claim 1-20 and 30-35 are rejected under 35 U.S.C. 103 as being unpatentable
`
`over Port et al. (US 2011/0092806)in view of Marnett (US 2005/0002859), in further
`
`view of de Vries (Current Pharmaceutical Design, 2006, 12, p. 3847-3856).
`
`Port and Marnett teach DOTA-NSAID (fenbufen, diflunisal, sulindac) conjugates
`
`for imaging, including MRI, as set forth above.
`
`Port and Marnett do not specifically teach imaging and treatment of stroke.
`
`De Vries teaches that COX-2...
`
`is transiently induced during inflammation by
`
`various stimuli. Increasing evidence has shown that COX-2 is not only implicated in
`
`inflammation but also in oncogenesis. Overexpression of COX-2 has been observedin
`
`a variety of tumors. Prostaglandins produced by COX-2 affect important processesin
`
`carcinogenesis, including angiogenesis, tissue invasion, metastasis and apoptosis.
`
`Several studies indicate that COX-2 is also involved in neurological disorders, like
`
`Alzheimer’s disease, Parkinson’s disease and ischemia, where COX-2 overexpression
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 8
`
`leads to neurotoxicity. Many aspects of the role of COX-2 in (patho)physiology,
`
`however, remain unclear. At present, COX-2 expression is determined by ex vivo
`
`laboratory analysis, but the results could be greatly affected by the instability of COX-2
`
`mRNA and protein and by sampling errors. A noninvasive imaging method to monitor
`
`COX-2 expression, like positron emission tomography (PET) or single photon emission
`
`computed tomography (SPECT), could overcome this complication and mayprovide
`
`novel insights in the role of COX-2, especially in neurological disorders whererepetitive
`
`sampling is not possible (abstract).
`
`[99mTc]diflunisal is an example of a COX-2 inhibitor that has been labeled with a
`
`radioactive isotope for PET or SPECT imaging.
`
`See pages 3851 and 3854 directed to COX-2 upregulation in cerebral ischemia /
`
`stroke.
`
`Since its discovery in the early 1990’s, COX-2 has been the subject of extensive
`
`research that implicates the enzyme in the initiation and progression of a variety of
`
`diseases that are generally associated with inflammation, neurodegeneration and
`
`cancer. This led to the general recognition that COX-2 is an interesting target for
`
`pharmacological treatment and prevention of these diseases. Although many aspects of
`
`the mechanism of action of COX-2 in physiology and diseasearestill unknown,
`
`encouraging treatment results with COX-2 inhibitors have already been obtained. A
`
`noninvasive imaging method for COX-2 maynot only give moreinsight in its role in
`
`disease, but could also provide a useful clinical tool for diagnosis, patient selection,
`
`monitoring of disease progression and therapy evaluation. Such a technique could also
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 9
`
`be applied to determine the pharmacokinetics and in vivo binding characteristics of new
`
`COX-2 inhibitors.
`
`It would have been obvious to one of ordinary skill in the art at the time of the
`
`invention to extend the teaching of inflammation targeted MRI imaging using the DOTA-
`
`COX-2 inhibitor compoundsof Port and Marnett when the teachings of Port and Marnett
`
`are taken in view of de Vries. Each of Port, Marnett and de Vries are directed to
`
`imaging related to COX-2 expression using labeled COX-2 inhibitors. One would have
`
`been motivated to provide the compounds of Port and Marnett for imaging/therapyof
`
`brain inflammation to include stroke, with a reasonable expectation of success, because
`
`de Vries teaches that COX-2 is upregulated in cerebral ischemia / stroke.
`
`Response to arguments
`
`Applicant argues that each compound has a gadolinium complex(left side of
`
`compound), a polycyclic component (right side of compound), and a middle or linking
`
`portion that links the gadolinium complex with the polycyclic component. The middle or
`
`linking portion includes two secondary amides separated by a CH2-CH2 group. Notably,
`
`and other than the two secondary amides, neither the middle or linking portion nor the
`
`polycyclic component includes any additional nitrogen atoms. Applicant asserts that the
`
`compounds at page 50 of Port include the gadolinium complex, a linker portion, anda
`
`polycyclic portion, but none of these compounds disclose or suggest Applicant’ s
`
`claimed Chemical Formula 2, 3, or 4.
`
`Applicant's arguments have beenfully considered but are not found to be
`
`persuasive. With regard to the structure of the compound, it is noted that Port at page
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 10
`
`50 teachesthe claimed chelate (DOTA)and linker. Any additional atoms are due to the
`
`structure of the biovector itself (e.g. folic acid). While the DOTA-fenbufen and DOTA-
`
`diflunisal conjugates do not specifically recite the claimed linker, Port teaches that a
`
`variety of linkers can be used between the chelate and biovector. One could have
`
`readily substituted another exemplified linker, a (CH2CONHCH2CHz2)linker, as a
`
`functionally equivalent linker between the chelate and biovector with a reasonable
`
`expectation of success in providing a chelator-linker-biovector compoundfor use in
`
`imaging. For example, conjugation of fenbufen or diflunisal via the carboxylic acid,
`
`analogous to the conjugation of folic acid, to the chelate/linker on the compoundof Port
`
`at page 50 would readily result in the claimed compounds.
`
`Applicant further argues that Port does not teach or suggest that any of the
`
`compounds areanti-inflammatory compounds. It is noted that Port doesindicate at
`
`paragraph [0257] that the biovector may target COX,but Port does not teach that the
`
`biovector has anti-inflammatory properties. Port simply notes that the biovector may
`
`target COX or other enzymes, e.g., metalloproteases and tyrosine kinase. Marnett
`
`specifically refers to COX-2 targeted imaging agents. One of skill in the art would not
`
`combine Marnett with Port because Port is unconcerned with COX-2 agents or anti-
`
`inflammatory activity. De Vries does nothing to overcome the deficiencies of the
`
`primary combination of Port and Marnett.
`
`Applicant’s arguments have been fully considered but are not found to be
`
`persuasive. Port specifically exemplifies fenoufen and diflunisal as biovectors as well
`
`as teaching COXselective ligands to be suitable biovectors. Port teachesthat
`
`fenbufen, diflunisal and sulindac are COX-2-selective ligands which are derivatives of a
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 11
`
`non-steroidal anti-inflammatory drug (NSAID). Further, a composition andit’s properties
`
`are inseparable, see MPEP 2112. Both Port and Marnett teach overlapping NSAID
`
`derivatives (fenbufen and diflunisal) conjugated to an imaging agent. The class of drug
`
`is known from the name to be anti-inflammatory.
`
`Applicant further argues that with regard to claim 15, there is no teaching that the
`
`compound targets a brain inflammation site and has anti-inflammatory activity on the
`
`brain inflammation site.
`
`Applicant's arguments have been fully considered but are not foundt o be
`
`persuasive.
`
`It is submitted that De Vries teaches the association between COX-2 and
`
`inflammation, cerebral ischemia / stroke, for example COX-2 has been the subject of
`
`extensive research that implicates the enzyme in the initiation and progression of a
`
`variety of diseases that are generally associated with inflammation, neurodegeneration.
`
`A labeled NSAID, diflunisal, is taught and further teaching that labeled COX-2 is a target
`
`for pharmacological treatment and prevention of these diseases. One would have been
`
`motivated to provide the compounds, labeled NSAIDs, of Port and Marnett for
`
`imaging/therapy of brain inflammation to include stroke, with a reasonable expectation
`
`of success, because de Vries teaches that COX-2 is upregulated in cerebral ischemia /
`
`stroke.
`
`Conclusion
`
`No claims are allowed atthis time.
`
`Any inquiry concerning this communication or earlier communications from the
`
`examiner should be directed to LEAH H SCHLIENTZ whosetelephone number is
`
`

`

`Application/Control Number: 16/982,856
`Art Unit: 1618
`
`Page 12
`
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`
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`
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`
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`
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`
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`
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`
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`
`/LHS/
`
`/Michael G. Hartley/
`Supervisory Patent Examiner, Art Unit 1618
`
`