DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's amendment and remarks, filed 2/13/26, are acknowledged.
Claims 1, 5, 9-10, 17-18, 20-21, 32, 38-40 have been amended.
Claims 1-3, 5, 9-10, 17-18, 20-21, 31-32, 38-46 are pending.
Claims 39 and 41-45 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to non-elected species.
Claims 1-3, 5, 9-10, 17-18, 20-21, 31-32, 38, 40 and 46 read on the elected invention and are being acted upon.
The use trademarks has been noted in this application (e.g. NANOBODYTM.). Each letter of the trademarks should be capitalized wherever it appears and be accompanied by the generic terminology. Although the use of trademarks is permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as trademarks.
Upon reconsideration, and in view of Applicant’s claim amendments, the rejection under 112b is withdrawn.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5, 9-10, 17-18, 20-21, 31-32, 38, 40 and 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of DUB binders and target protein binders.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See MPEP 2163.
The instant claims are directed to a bivalent molecules comprising any target protein binder and a binder of any DUB, wherein the DUB binder is a single domain or antibody mimetic. The claims encompass a large genus of structurally distinct binders. For example, an antibody mimetic would encompass an aptamer (nucleic acid) or a peptide, or even a single CDR of an antibody. Furthermore, the claims encompass binders that are functionally distinct and bind to any DUB, which encompasses an enormous genus of structurally and functionally distinct proteins. Likewise, the claims encompass a large genus of functionally distinct target proteins. There is no art recognized correlation between structure and binding function as broadly claimed. For example, the state of the art is such that antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. For example, see Janeway which teaches that the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. For kappa light chains, there are approximately 40 functional V gene segments and five J gene segments, and thus potentially 200 different Vkappa regions. Janeway teaches that for lambda light chains, there are approximately 30 functional V lambda segments and four J gene segments yielding 12 possible V lambda regions, so in all 320 different light chains can be make as a result of combination different light chain gene segments. These can also be further varied by a process of somatic hyper mutation. Furthermore, the diversity of the immunoglobulin repertoire is mediated in part by different combination so heavy and light chain V regions that pair to form a unique antibody binding site. See, for example, Rabia, 2018, which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4). The only species of DUB binder discloses are the NANOBODYTM sequences of SEQ ID NO: 1-6, with the CDR1-3 of SEQ ID NO: 7-24, as recited in claims 9-10. The only species of target binder, or CFTR binder disclosed are the NANOBODYTM sequences of SEQ ID NO: 25-38, with the CDR1-3 of SEQ ID NO: 39-80, as recited in claims 20-21. These are not sufficiently representative of the broad genus of different DUB binders or target/CFTR binders encompassed by the present claims. For example, the present claims encompass antibody mimetics, but no species are disclosed. The present claims encompass binders that bind to any target protein and a genus of different DUB, whereas only a limited number of NANOBODYTM sequences that target CFTR or a single DUB are disclosed.
The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus binders encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3.
Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Applicant’s arguments filed 2/13/26 have been fully considered, but they are not persuasive.
Applicant argues that the specification discloses single domain antibodies that bind a deubiquitinase and provides twenty different target single domain binders which is sufficiently representative of the claimed genus,.
The instant specification in Table 1 discloses 6 species of NANOBODY, i.e. VHH that bind to an DUB USP family member. This not sufficiently representative of the instant claims. For example, the instant claims encompass single domain antibodies that bind to a wide genus of structurally different DUB family members including UCH, Josephin, MINDY and JAMM family members. Furthermore, the claims are not limited to single domain antibodies, but broadly encompass any antibody mimetic. No species of antibody mimetic are disclosed. Furthermore, the specification discloses certain VHH antibodies that bind to CFTR, while the claims broadly encompass any single domain antibody or antibody mimetic that binds to any target protein. The disclosed species are not sufficiently representative of the broad genus of binders encompassed by the instant claims..
Applicant further argues that as of the priority date of the instant application, a variety of single domain antibodies were known/used to specifically bind deubiquitanse and target proteins.
Applicant cites no evidence as the availability of single domain antibodies. Furthermore, the claims are not limited to single domain antibodies, but broadly encompass any antibody mimetic.
It is noted that claims 9-10 and 20-21 were inadvertently omitted from the heading the rejection, which was a typographical error, since the body of the rejection clearly set forth that the subject matter encompassed in the claims was lacking written description (claims 20-21 encompass any DUB binder, such as an antibody mimetic, claims 9-10 encompass any target binding, including an antibody mimetic, which lack written description for the reasons set forth above).
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 31, 38, and 46 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2022/0160890.
The ‘890 publication teaches a chimeric molecule comprising a first binding domain that binds to a ubiquitinated protein target (i.e. a target protein binder), a second binding domain that binds to a DUB (i.e. a DUB binder), and a linker between the first and second binding domain (See pages 1, 3, and Fig. 1, in particular). The chimeric molecule comprises two different binding domains and hence is a bivalent molecule (see also paragraph 189 of the ‘890 publication which teaches that the chimeric molecules are bispecific, i.e. bivalent). The ‘890 publication teaches that the first binding domain and the second binding domain can be a an antibody fragment i.e. an “antibody mimetic” (see pages 1-2 and 19, in particular). The ‘890 publication teaches that the antibody fragment can be a single chain antibody containing the variable heavy and light chain region linked by a linker, i.e. an scFv (see page 19, in particular). The ‘890 publication teaches that the DUB is from the ovarian tumor protease family (i.e. an “endogenous” DUB, see page 2, in particular). The ‘890 publication teaches the chimeric molecule targets a DUB enzyme that is capable of deubiquitinating the ubiquitinated target protein. (i.e. the target protein is a substrate for deubiquitinating by the DUB, see page 3, in particular). The ‘890 publication teaches the target protein can be CFTR (See page 4 and Example 4, in particular).
Applicant’s arguments filed 2/13/26 have been fully considered, but they are not persuasive.
Applicant argues that the amendments overcome the rejection.
As noted above, the ‘890 publication teaches that the first and second binding domains can be antibody fragments, which would be within the scope of an “antibody mimetic”. The ‘890 publication also teaches that the first and second binding domain can be a peptide or aptamer, which would also be within the scope of an “antibody mimetic”.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth 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.
Claim 1-3, 5, 17-18, 31-32, 38, 40 and 46 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0160890, in view of Ingram, Feb. 2018.
The teachings of the ‘890 publication are described above.
The reference differs from the claimed invention in that it does not explicitly teach a single domain antibody
Ingram teaches that single domain antibodies are an advantageous type of antibody fragment that are small in size, can properly maintain function when expressed in the cytosol, and are excellent substrates for construction of fusion proteins and for facilitating protein-protein interactions (see pages 695 and 704, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a single domain antibody as taught by Ingram, as the antibody fragment in the chimeric molecules of the ‘890 publication. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because Ingram teaches that they , are an advantageous type of antibody fragment that are small in size, can properly maintain function when expressed in the cytosol, and are excellent substrates for construction of fusion proteins and for facilitating protein-protein interactions
Applicant argues that the ‘890 publication is entirely prophetic and that therefore there would be no motivation to modify the molecules of the ‘890 publication with a reasonable expectation of success.
References may be relied upon for all that they suggest to the ordinary artisan and proof of efficacy is not required. See MPEP 2121 and 2143.02. A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; “proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation.” Impax Labs. Inc. v. Aventis Pharm.Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006) (citing Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326, 75 USPQ2d 1297, 1302 (Fed. Cir. 2005)). Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019).
The ’890 publication provides guidance for constructing the chimeric molecules with diagrams in Figs. 1-5, details on the types of linkers, and constructing a chimeric protein having the desired components using well known molecular biology techniques would be well within the purview of the ordinary artisan.
It is also noted that the teachings of the instant specification are no more detailed than the prior art, in that the present claims broadly encompass a large genus of structurally distinct antibody mimetics targeting a genus of proteins that have not been reduced to practice nor is an “proof” of efficacy disclosed.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5, 17-18, 31-32, 38, 40 and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9-16, and 20 of copending Application No. 19/391,937, in view of US 2022/0160890 and Ingram, Feb. 2018.
The ‘937 application claims a bivalent molecule comprising a DUB binder a target binder and a variable linker between the DUB binder and the target binder. The ‘937 application claims that the DUB is endogenous and is a an OTU family member and that the target binder binds CFTR (i.e. target substrate protein for deubiquitinating by the DUB). The ‘937 application does not specifically claim that the DUB binder and target binder are a single domain antibody. However, it would be obvious to use an antibody fragment such a single domain antibody in the bivalent molecules based on the teachings of the ‘890 publication and Ingram, 2019 for the same reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
It is noted that the 17/864,382 application was abandoned and refiled as 19/391,937 and the heading of the rejection has been updated, accordingly.
Applicant argues that the claims are not obvious for the same reasons set forth above.
The claims stand rejected for the same reasons set forth above.
The following are new grounds of rejection necessitated by Applicant’s claim amendments.
Claims 1-3, 5, 9-10, 17-18, 20-21, 31-32, 38, 40 and 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The specification and the claims as originally filed do not provide support for the invention as now claimed, specifically:
A bivalent molecule wherein the DUB binder and target protein binder are “single domain antibody” (Claim 1, and dependent claims).
A review of the specification fails to reveal support for the new limitations.
The term single domain antibody, as used in the art, refers to a genus of different antibody fragments that can include camelid single domain antibodies that consist of a heavy chain only antibody fragment or VHH (i.e. NANOBODYTM), VNARs, as wells as human single domain antibodies that consist of a VH or VL only antibody fragment (see Hussack, 2012, and Ingrahm, of record). The instant specification discloses NANOBODYTM, but this is trademark term that describes camelid single domain antibodies consisting of a heavy chain only antibody fragment or VHH (see also paragraph 80 of the specification wherein GFP NANOBODYTM is denoted in parenthesis as VHH). The specification also discloses a dAb fragment which consists of a VH domain (i.e. a VH single domain antibody, see paragraphs 52-53 of the specification). However, the specification does not disclose “single domain antibodies” as broadly recited in the present claims. The art recognized meaning of “single domain antibodies” would encompass a single VL domain, and nowhere does the specification contemplate a single VL domain antibody. Amendment to recite a VHH or a VH single domain antibody, for example, would be remedial.
No claim is allowed. The sequences in claims 9-10 and 20-21 are free of the prior art. Amendment to claim 1 to remove the recitation of “antibody mimetic”, to recite a VH single domain antibody, and to incorporate both claims 9 and 20 (or 10 and 21), would overcome the rejections of record and would be allowable subject matter.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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