Notice of Pre-AIA 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 .
Claim Status
Claims 1-25 are pending and under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/28/2025 is being considered by the Examiner. The signed IDS forms are attached with the instant office action.
It is noted that NPL document number 248 contains unnecessary extra wording at the end.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at paragraph [0213] at page 66. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because they depict nucleic acid and/or amino acid sequences “GGGGS” and “GGGGGS” in the third from last line of paragraph [0275] at page 83, which are not identified by sequence identification numbers. Applicant must provide appropriate amendments to the specification inserting the required sequence identifiers.
Appropriate action correcting this deficiency is required. If any sequences are not in the current sequence listing, Applicant must submit paper and computer-readable copies of a substitute sequence listing, together with an amendment directing its entry into the specification and a statement that the content of both copies are the same and, where applicable, include no new matter.
Sequences appearing in the specification and/or drawings must be identified by a sequence identifier in accordance with 37 C.F.R. 1.821(d); sequence identifiers for sequences appearing in the drawings may appear in the drawings or in the brief description of the drawings.
Appropriate correction is required.
Claim Objections
Claim 3 is objected to because of the following informalities: “the multispecific construct” in line 5 should read “the multispecific polypeptide construct” because claim 1 recites “a multispecific polypeptide construct”. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: “selected from the group consisting of a sdAb or an scFv” in line 3 should read “selected from the group consisting of a sdAb and an scFv” for proper Markush group. See MPEP 2173.05(h) for proper Markush group format. Appropriate correction is required.
Claims 4-5 and 24 are objected to as being dependent from rejected base claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17 and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 17 recites “SEQ ID NO: 31” in the last line, but the recited amino acid sequence is not SEQ ID NO: 31. It is SEQ ID NO: 315 as evidenced by paragraph 195 at page 58 of instant specification. Therefore, it is unclear which SEQ ID NO Applicant intends to recite.
Claim 21 recites “anti-CD3 Fv” in line 1. There is insufficient antecedent basis for this limitation in the claim. While claim 1 recites “anti-CD3 dsFv”, claim 1 does not recite “anti-CD3 Fv”.
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 21-22 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 “written description” rejection.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Regents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to antigen, high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 (“[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims.”). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
Additionally, “An adequate written description must contain enough information about the actual makeup of the claimed products—“a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” which may be present in “functional” terminology “when the art has established a correlation between structure and function.” Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies.” Amgen Inc v. Sanofi 124 USPQ2d 1354, 1361 (Fed. Cir. 2017). “Further, the “newly characterized antigen” test flouts basic legal principles of the written description requirement. Section 112 requires a “written description of the invention.” But this test allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen. The test thus contradicts the statutory “quid pro quo” of the patent system where “one describes an invention, and, if the law's other requirements are met, one obtains a patent.” Ariad, 598 F.3d at 1345.” Amgen at 1362.
Claim Analysis
Claim 21 recites “a sequence that exhibits at least 90% sequence identity to any of SEQ ID NOS: 44, 49-62, 290, and 311” in line 3-4 and “a sequence that exhibits at least 90% sequence identity to any of SEQ ID NOS: 64, 72, 74, 76, 78-81, 241 and 289” in line 6-7. Likewise, claim 22 recites “a sequence that exhibits at least 90% sequence identity to SEQ ID NOS: 44” in line 2-3 and “a sequence that exhibits at least 90% sequence identity to SEQ ID NO: 72” in line 4-5. Therefore, 10% or less sequence variation can occur within CDR sequences of VH and VL sequences because claims 1 and 21-22 do not define 6 CDR sequences. A skilled artisan in the art would recognize that the specificity of an antibody is dependent upon six specific CDR sequences and different combinations of CDR sequences greatly alter antigen binding. Instant specification did not disclose any polypeptide construct comprising 10% sequence variation within CDR sequences of VH and VL sequences of anti-CD3 dsFv which still binds to CD3 as required by instant claims 21-22. Therefore, VH and VL sequences of anti-CD3 dsFv disclosed by instant specification cannot be considered as a representative number of species falling within the scope of genus encompassing sequence that exhibits at least 90% sequence identity to VH and VL sequences recited by instant claims 21-22.
The disclosure therefore does not show that applicant was in possession of the necessary common attributes or features possessed by the members of the claimed genus. Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
It is suggested that Applicant cancel claim limitation “a sequence that exhibits at least 90% sequence identity to any of SEQ ID NOS: 44, 49-62, 290, and 311” in line 3-4 of claim 21; “a sequence that exhibits at least 90% sequence identity to any of SEQ ID NOS: 64, 72, 74, 76, 78-81, 241 and 289” in line 6-7 of claim 21; “a sequence that exhibits at least 90% sequence identity to SEQ ID NOS: 44” in line 2-3 of claim 22; and “a sequence that exhibits at least 90% sequence identity to SEQ ID NO: 72” in line 4-5 of claim 22 to overcome this rejection.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
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 present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 6-13, 15-16, 18-20 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moore et al (US2014/0294823; 1/28/2025 IDS) in view of Nagorsen et al (Pharmacology & Therapeutics 136 (2012) 334-342; PTO-892).
Regarding claims 1, 6, 8, 10-11, 15-16, 18-20 and 25, Moore teaches a bispecific construct comprising a first component comprising an immunoglobulin Fc region and a second component comprising a CD3-binding region, wherein the CD3 binding region is Fv antibody fragment comprising a variable heavy chain (VH) and a variable light chain (VL); the Fc is a heterodimeric Fc comprising a first Fc polypeptide and a second Fc polypeptide and the VH and VL of the anti-CD3 antibody or antigen binding fragment are linked to opposite polypeptides of the heterodimeric Fc; wherein the Fc region is positioned N-terminal to the CD3-binding region; and the first component comprises a Fab against CD19, which is a tumor associated antigen (TAA) (sheet 132 of 160, Figure 64; reproduced below).
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Moore teaches (GGGGS)X3 linker which is same amino acid sequence as SEQ ID NO: 170 of instant claim 11 (figure 67) and comprises GGGGS (SEQ ID NO: 170 of instant claim 20). Moore teaches “As is generally depicted the Figures, the fusion partners are depicted as A, B, C and D, with all combinations possible. In general, A, B, C and D are selected such that the heterodimer is at least bispecific or bivalent in its ability to interact with additional proteins” (paragraph 120). Moore teaches “Virtually any antigen may be targeted by the immunoglobulins herein, including but not limited to proteins, subunits, domains, motifs, and/or epitopes belonging to the following list of target antigens, which includes both soluble factors such as cytokines and membrane-bound factors, including transmembrane receptors: 17-IA, 4-1BB, …” (paragraph 239). Therefore, Moore teaches multispecific polypeptide construct comprising anti-CD19 antibody (TAA-binding domain) and 4-1BB-binding domain (CRBR) as A and B component of Figure 64 (Moore; sheet 132 of 160). Moore’s construct corresponds to construct of claim 6(iii). Moore teaches that the molecules may be stabilized by the incorporation of disulfide bridges linking the VH and VL domains (paragraph 208).
Regarding claim 7, Moore teaches “knobs and holes” variants, “charge pairs” variants as well as “pI variants” (paragraph 109).
Regarding claim 9, Moore teaches the peptidyl linker cleavable by an intracellular protease (paragraph 313).
Regarding claim 12, Moore’s construct comprises Fab fragment as claimed by instant claim 12.
Regarding claim 13, Moore teaches scFv anti-CD19 (Figure 67 and paragraph 165). Moore also teaches domain antibodies (paragraph 162).
The difference between prior art and the instant invention is that Moore does not teach stimulating or inducing an immune response against a target cell using the multispecific polypeptide construct.
Regarding claims 1, 6 and 25, Nagorsen teaches “A highly promising new drug candidate in late-stage clinical development for treatment of B cell malignancies is blinatumomab (MT103 or AMG 103). This bispecific antibody construct has dual specificity for CD19 and CD3 and belongs to the class of bispecific T cell engager (BiTE®) antibodies, which can potentially engage all cytotoxic T cells of a patient for redirected lysis of tumor cells. Here, we review how blinatumomab has so far been pre-clinically and clinically developed for the treatment of patients with non-Hodgkin's lymphoma and acute lymphoblastic leukemia.” (abstract). Bringing immune cell to close proximity of the cancer cell is one type of stimulating immune response against a target cell. Therefore, Nagorsen teaches treating cancer by stimulating immune response against a target cell by using CD19 X CD3 bispecific antibody.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used Moore’s construct comprising CD19, CD3 and 4-1BB to treat cancer because Nagorsen teaches treating cancer by stimulating immune response against a target cell by using CD19 X CD3 bispecific antibody. One of ordinary skill in the art would understand that Moore’s construct can bind to B-cell malignancy expressing CD19 and stimulate immune response via anti-CD3 portion interacting with T-cell in the patient. Therefore, one of ordinary skill in the art would be motivated to use Moore’s construct to treat B-cell malignancy. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because Nagorsen teaches treating cancer by stimulating immune response against a target cell by using CD19 X CD3 bispecific antibody. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Limiting the claims to the allowable products in the parent case, by adopting the same language as the allowed claims would obviate this rejection.
Double Patenting
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, 6-7, 10, 12-14, 17, and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. US12365728B2 (hereinafter patent’728; PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
Regarding claims 1-2, 6 and 12-14, Claim 31 of patent’728 claims “A method of stimulating or inducing an immune response in a subject, the method comprising administering, to a subject in need thereof, the pharmaceutical composition of claim 29.” Claims 11-29 of patent’728 claims multispecific polypeptide with same structure as instant claims.
Regarding claim 3, claim 17 of patent’728 claims “The DLL3-binding polypeptide construct of claim 11, wherein the at least one DLL3 VHH domain is positioned amino-terminally relative to the Fc region and/or carboxy-terminally relative to the CD3 binding region of the multispecific polypeptide construct.”
Regarding claim 7, claim 12 of patent’728 claims that each of the first and second Fc polypeptides of the heterodimeric Fc region comprise a knob-into-hole modification or comprise a charge mutation to increase electrostatic complementarity of the polypeptides.
Regarding claim 10, claim 22 of patent’728 claims that the linker is a non-cleavable linker.
Regarding claim 17, the first species of claim 15 of patent’728 claims “the anti-CD3 antibody or antigen-binding fragment comprises: a VH CDR1 comprising the amino acid sequence TYAMN (SEQ ID NO: 29); a VH CDR2 comprising the amino acid sequence RIRSKYNNYATYYADSVKD (SEQ ID NO: 30); a VH CDR3 comprising the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO: 31), a VL CDR1 comprising the amino acid sequence RSSTGAVTTSNYAN (SEQ ID NO: 32); a VL CDR2 comprising the amino acid sequence GTNKRAP (SEQ ID NO: 33); and a VL CDR3 comprising the amino acid sequence ALWYSNLWV (SEQ ID NO: 34).” The first species of claim 15 of patent’728 corresponds to the first species of instant claim 17.
Regarding claim 23, the third species of claim 15 of patent’728 claims “a VH CDR1 comprising the amino acid sequence GFTFNTYAMN (SEQ ID NO: 461); a VH CDR2 comprising the amino acid sequence RIRSKYNNYATY (SEQ ID NO: 462); a VH CDR3 comprising the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO: 31), a VL CDR1 comprising the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO: 468); a VL CDR2 comprising the amino acid sequence GTNKRAP (SEQ ID NO: 469); and a VL CDR3 comprising the amino acid sequence ALWYSNHWV (SEQ ID NO: 464).”
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHEOM-GIL CHEONG whose telephone number is (571)272-6251. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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/CHEOM-GIL CHEONG/Examiner, Art Unit 1645
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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