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 .
DETAILED ACTION
Applicant’s election without traverse of Group I, claims 1, 2, 10, 11, 14, 15, 18, 19, 22, 36, 47, 48, and 73, as well as the species election of PD-L1 as a tumor-associated antigen (TAA), in the reply filed on 12/18/2025 is acknowledged.
Claims 1, 2, 10, 11, 14, 15, 18, 19, 22, 32, 36, 42, 47, 48, and 73 are pending.
Claims 32 and 42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/18/2025.
Claims 10, 11, 14, 15, 18, and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/18/2025.
Claims 1, 2, 22, 36, 47, 48, and 73 are under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 2, 22, 36, 47, 48, and 73 have an effective filing date of 06/014/2020, corresponding to PRO 63/034,822.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/07/2024, 09/16/2025, and 09/30/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Notes on the Prior Art
At the effective filing date of the invention, anti-ABCG2 antibodies were known in the art. For example Shi et al. (Stem Cell Research and Therapy, 9:144, 1-11, 2018) teach that “our findings reveal definitive evidence that the EPI-loaded MBs [microbubbles] conjugated with ABCG2 mAb plus therapeutic ultrasound can target MM [multiple myeloma] CSCs [cancer stem cells] to develop an effective therapy for MM.” See p. 10. Although anti-ABCG2 monoclonal antibodies may be used in the treatment of cancer, the prior art does not teach a bispecific antibody that binds to ABCG2 and a tumor antigen. Furthermore the prior art does not teach or suggest a bispecific antibody that binds to ABCG2 and tumor antigen, wherein the anti-ABCG2 binding moiety and the tumor antigen-binding moiety share a common light chain variable region. As such the claimed invention is free of the prior art.
Claim Objections
Claim 73 recites the antibody “Atezolizmumab,” which appears to be a typographical error that should read “Atezolizumab.” Appropriate correction is required.
Claim Rejections
35 U.S.C. 112(b)
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.
Regarding claims 2, 22, and 36, the phrase “optionally” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
35 U.S.C. 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.-Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 73 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 73 is drawn to an anti-ABCG2/anti-PD-L1 bispecific antibody comprising 1) a first VL that comprises the LCDRs 1-3 of SEQ ID NO: 1 and 2) a second VL that comprises the LCDRs 1-3 of Atezolizumab; however claim 73 depends from claim 1, which recites anti-ABCG2/anti-PD-L1 bispecific antibody having a common VL. As such claim 73 fails to limit the claim from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
35 U.S.C. 112(a)
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 1, 2, 22, 36, 47, and 48 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Claim 1 is drawn to a bispecific antibody molecule that binds ABCG2 and a tumor associated antigen (TAA), the antibody molecule comprising two identical variable light (VL) chains, a first variable heavy (VH) chain, and a second VH chain, wherein the VL chains each comprise an antigen-binding site for ABCG2, the first VH chain comprises an antigen-binding site for ABCG2, and the second VH chain comprises an antigen-binding site for the TAA, and wherein the second VH chain binds the TAA when paired with one of the VL chains, wherein the bispecific antibody binds to cancer cells expressing both ABCG2 and the TAA while showing reduced binding to non-cancer cells expressing ABCG2 and/or the TAA, or a pharmaceutical composition comprising said bispecific antibody molecule. As indicated above Applicant has elected PD-L1 as a species of tumor antigen. The claims encompass a large genus of antibodies having diverse heavy and light chain variable region amino acid sequences. Following a review of the specification, it appears that six species within the claimed genus have been prepared, specifically, a bispecific antibody comprising 1) the VL (SEQ ID NO: 1 or 59) and the VH (SEQ ID NO: 5, 6, or 7) of the anti-ABCG2 antibody 5D3 and 2) the anti-PD-L1 VH of SEQ ID NO: 27; however in view of this disclosure, Applicant is claiming a broad genus of molecules that would be expected to encompass numerous anti-ABCG2 VHs, numerous anti-PD-L1 VHs, and numerous common VLs. Even though Applicant has disclosed six species within said genus, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequences (and combinations of said CDR sequences) give rise to anti-ABCG2 VHs, anti-PD-L1 VHs, and common VLs that form an anti-ABCG2/anti-PD-L1 bispecific antibody having a common VL. As detailed below Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and as such Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A “representative number of species” means that the species which are adequately described are representative of the entire 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. In the instant case, Applicant has disclosed six species within the genus claimed; however given the substantial antibody structure variation within the genus, as well as the high level of unpredictability in the art, the disclosure of six species comprised within the claimed genus is not sufficiently representative of the entire genus.
Furthermore Applicant has not disclosed which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise CDRs that form an anti-ABCG2/anti-PD-L1 bispecific antibody having a common VL, because the instant specification does not provide structural antibody features that correlate with a functional ability to bind ABCG2 or PD-L1. To elaborate on why the claimed antibodies lack adequate written description, Mariuzza (Annu. Rev. Biophys. Biophys. Chem., 16: 139-159, 1987) reviews the structural basis of antigen-antibody recognition and teach that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure that fully comprises six CDRs, three each from the light and heavy chains. The amino acid sequences of the CDRs are hypervariable, as the amino acid residues contained within the CDRs determine much of the antibody’s antigen-binding specificity. In view of Mariuzza, it is apparent that antibodies having less than all six CDRs that form the antigen binding site of a conventional antibody in their proper context of heavy and light chain variable domains do not describe the particularly identifying structural feature of the antibody that correlates with the antibody’s ability to bind antigen. Absent a description of the at least minimal structural features correlating with a functional ability to bind ABCG2 and PD-L1 which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise CDRs that form an anti-ABCG2/anti-PD-L1 bispecific antibody having a common VL.
Furthermore while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example in a series of experiments involving a monoclonal antibody to Legionella pneumophilia serotype 1, McCarthy et al. (J. Immunol. Methods, 251(1-2): 137-149, 2001) demonstrated that a single VH CDR3 substitution of tyrosine to serine at position 95 resulted in the total loss of antigen recognition in an ELISA. Lin et al. (African Journal of Biotechnology, 10(79):18294-18302, 2011) teach that a single amino acid substitution in the VL CDR3 of an anti-avian infectious bronchitis virus (IBV) single-chain antibody (ZL.80) may abrogate binding. For example at Figure 3, Lin et al. demonstrate that replacing either the Cys105 or Asp106 residue in the VL CDR3 of ZL.80 with an alanine residue reduces binding to near negative control levels. Lin et al. also teach that some single amino acid substitutions in the VL CDR3 of ZL.80 may significantly improve binding. For example replacing the Val108 residue in the VL CDR3 of ZL.80 with a tyrosine residue results in a 12.9-fold increase in affinity compared to parental ZL.80. Accordingly absent empirical determination, one skilled in the art would be unable to predict or envision which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise CDRs that form an anti-ABCG2/anti-PD-L1 bispecific antibody having a common VL.
Although screening techniques can be used to isolate an anti-ABCG2/anti-PD-L1 bispecific antibody having a common VL, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
It is further noted that Applicant has not disclosed which heavy and light chain CDR amino acid sequences (or combinations thereof) may be combined such that the resultant heavy and light chain variable regions comprise CDRs that form an anti-ABCG2/anti-PD-L1 bispecific antibody having a common VL, wherein the bispecific antibody binds to cancer cells expressing both ABCG2 and PD-L1 while showing reduced binding to non-cancer cells expressing ABCG2 and/or PD-L1.
Claim 2 is included in this rejection, because the claim encompasses variable regions having variability within the CDR regions. For example claim 2 recites that the VL chains comprise an amino acid sequence having at least 90%, 95%, or 99% sequence homology with SEQ ID NO: 1 or SEQ ID NO: 59, and claim 2 also recites that the VH chains comprise an amino acid sequence having at least 90%, 95%, or 99% sequence homology with SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7.
Claim 22 is included in this rejection, because the claim encompasses variable regions having variability within the CDR regions. For example claim 22 recites that the VH chains comprise an amino acid sequence having at least 90%, 95%, or 99% sequence homology with SEQ ID NO: 27.
Claims 36, 47, and 48 are included in this rejection, because these claims ultimately depend from claim 1 but do not cure the deficiencies of claim 1 with respect to 35 U.S.C. 112(a).
Accordingly given the unpredictability associated with antibody CDR region changes on antigen binding and given the lack of particularity with which the claimed bispecific antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the specification would not reasonably convey to the skilled artisan that Applicant was in possession of the claimed invention at the time the application was filed.
Nonstatutory 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, 22, 36, 47, and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 64, 71, and 72 of copending Application No. 17/998,773 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other, because both sets of claims recite an anti-ABCG2/anti-PD-L1 bispecific antibody having a common VL and having identical anti-PD-L1 VH CDRs, as well as associated pharmaceutical compositions that comprise a pharmaceutically acceptable excipient and an additional active agent, such as a chemotherapeutic agent, an inhibitor of a multidrug resistance transporter, or an immunotherapy agent.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F, 9:00-6:00 EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642