DETAILED ACTION
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 .
Response to Amendment
Applicant’s amendment filed 17 February 2026 has been received and entered. Claims 1, 7, 9, 10 and 26 have been amended, claim 27 has been newly added and claims 4, 6, 12, 18-19 and 24-25 have been canceled. Claims 1-3, 5, 7-11, 13-17, 20-23 and 26-27 are currently pending.
The text of those sections of Title, 35, U.S. Code not included in this action can
be found in a prior Office action.
Any objection or rejection of record which is not expressly repeated in this action
has been overcome by Applicant's response and withdrawn.
Applicant's arguments filed 17 February 2026 have been fully considered but are not found to be persuasive.
Election/Restrictions
Claims 13-15, 17 and 20-23 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06 August 2025. The restriction requirement was made final in the Office action mailed 01 December 2025.
Drawings
The drawings were received on 17 February 2026. These drawings are not acceptable. The drawings are still objected to for the reasons noted in the previous Office action.
The Figures do not comply with 37 CFR 1.84(a)(1) because many of the Figures appear to use gray-scale which results in text, lines and symbols which are not solid black lines as required. See Figures 3, 5-11, 14-23. See screenshot below for illustrative purposes:
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The Figures do not comply with 37 CFR 1.84(b)(1) which requires photographs must be of sufficient quality so that all details in the photographs are reproducible in the printed patent. The text is blurry, some of the features are not clearly visible and the font size is problematic. See Figure 2. See screenshot example below:
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The Figures do not comply with 37 CFR 1.84(l) which requires that all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. Figure 3 is somewhat better than the previous version of the figure, but still not compliant as the text is not black and the value of “6.’91” seems to be an artifact from the previous version…it is not clear what the “ ‘ “ is meant to symbolize. See screenshot below for illustrative purposes:
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Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Response to Arguments
Applicant asserts at page 8 that “black and white line drawings are not absolutely required according to MPEP 6.08.02”. Applicant’s argument has been fully considered, but is not found persuasive. First, there is no “MPEP 6.08.02”. There is no form paragraph “6.08.02”. A review of MPEP 608.02 did not find support for Applicant’s assertion regarding black and white line drawings. MPEP 608.02 clearly sets forth that “there are two acceptable categories for presenting drawings in utility and design patent applications” which are (1) black ink and (2) color (see 37 CFR 1.84). Applicant is invited to point out the basis for the assertion regarding the nature of drawings which are acceptable in the MPEP.
Specification
The disclosure is objected to because of the following informalities: The newly filed substitute specification does not reflect the amendments which were introduced from the 12 May 2025 substitute specification and 09 April 2025 substitute specification. The specification was amended on 12 May 2025 to correct deficiencies related to the Sequence rules (correction of the incorporation statement at page 1) and amended on 09 April 2025 to include missing sequence identifiers (page 3 and 24).
The most recent substitute specification has reverted back to the original text of the specification from 12 July 2022 as there is no incorporation statement and pages 3 and 24 are missing sequence identifiers.
The substitute specification filing is defective because the marked-up copy of the specification does not show all the changes from the most recent specification filing (12 May 2025). In addition, the instant application is also no longer in compliance with the Sequence rules.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
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 1-3, 5, 7-10 and 26 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is directed to a bispecific antibody (or antigen-binding portion thereof) comprising a PD-L1 antigen binding moiety associated with a VEGF antigen-binding moiety. The VEGF antigen-binding moiety of the claim has written description. The PD-L1 antigen binding moiety comprises a CDR1 having the amino acid sequence of SEQ ID NO:1, a CDR2 having the amino acid sequence of SEQ ID NO:2 and a CDR3 having the amino acid sequence of SEQ ID NO:3. The specification states at 1.3 (page 41) that anti-PD-L1 VHH antibody (W3156-AP3R2-1A3-z12) was generated “by immunizing Alpacas with extracellular domain of human PD-L1 and mouse PD-L1 alternately, and PBMCs were isolated for phage library construction. After panning, screening and sequencing, one unique positive VHH fragment was identified”.
The instant specification fails to describe an anti-PD-L1 single-domain antibody which binds PD-L1 which does not possess the amino acid sequence of SEQ ID NO:4. SEQ ID NO:4 is the complete amino acid sequence of the VHH which includes not only the 3 CDRs but also the necessary framework such that the CDRs are positioned correctly to effect binding and the ability to block the interaction of PD-L1 with PD-1. The specification fails to describe any anti-PD-L1 single-domain antibody which comprises 3 CDRs but with no defined framework. The specification also fails to describe the full scope of anti-PD-L1 single-domain antibodies comprising 3 CDRs having the amino acid sequences of SEQ ID NO:1-3 with variations in framework regions as recited in claim 2 (85%, 90% or 95% sequence identity to SEQ ID NO:10).
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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.).
In the instant application, the specification discloses one VHH molecule which binds PD-L1 which is called W3156-AP3R2-1A3-z12 and has the amino acid sequence of SEQ ID NO:10. There is no disclosure of any PD-L1 antigen-binding moiety comprising the recited 3 CDRs of SEQ ID NO:1-3 with generic framework or lacking framework or possessing framework of SEQ ID NO:10 with up to 15% variation. There is no disclosure that the CDRs of SEQ ID NO:1-3 could be combined with any variable domain framework such as non-VHH framework and still result in a functional VHH antibody. There is also no disclosure of modifications to the VHH framework possessed by W3156-AP3R2-1A3-z12 which result in a functional VHH which binds PD-L1. Therefore, the specification does not describe representative species which fall within the context of the currently drafted claims
It is well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. Based on the instant disclosure one of skill in the art would not know which structures are essential for providing the binding ability and inhibition activity for the claimed anti-PD-L1 single domain antibody. For example, there is insufficient guidance based on the reliance of VHH antibodies to direct a person of skill in the art to select or to predict variable domain framework or to modify existing framework of the isolated VHH. Mere idea of function is insufficient for written description; isolation and characterization at a minimum are required.
Regarding VHH camelid antibodies, it was known in the prior art that these single domain antibodies are either in their native form not interacting with other variable domains, in the case of VHH or the variable domain must be modified, i.e. rendered hydrophilic, in the region which is normally interacting with the corresponding VL or VH chain, in order to avoid aggregation and loss of binding capacity (i.e. functionality) of the non-Camelid single variable domain. Muyldermans and Lauwereys (Journal of Molecular Recognition, 1999. Vol. 12, pages 131-140) teach the structure of a functional heavy chain antibody (camelid) contains a VHH domain, hinge, CH2 and CH3 domains (see figure 1). Additionally, Muyldermans and Lauwereys teach that naturally occurring heavy chain antibodies in humans or mice are not functional due to a deletion in the CH1 and hinge regions (page 133, 2nd column). One of ordinary skill in the art can conclude that framework from human and mice immunoglobulins would not be sufficient to provide functionality to camelid antibodies. Konning et al. (Curr. Opin. Struct. Bio. 45: 10-16, 2017) teach that VHH domains comprise different structural elements from VH and VL domains which result in a unique and stabilized structure (see page 11, column 2). Harmsen and Haard (Applied Microbiology and Biotechnology, 2007. Vol. 77, pages 13-22) teach that functional VHH domains contain four framework regions and three CDRs as in antibody heavy chains (page 14, 1st column). Harmsen et al. also disclose that VHHs can be classified into at least four distinct subfamilies (see page 588, column 2, paragraph 2) which differ from classical VH domains. Saerens et al. (J. Mol. Biol. 352:597-607, 2005) demonstrate that even a single amino acid difference in framework can abolish binding activity (see page 599, column 2, final paragraph).
In the absence of sufficient guidance and direction to the structural and functional analysis, Applicant's reliance on the VHH domains in the specification as filed does not appear to provide sufficient written description for the genus of anti-PD-L1 single domain antibodies encompassed in the claims and part of the claimed bispecific antibody in view of the above evidence, which indicates ordinary artisans could not predict the operability of the invention of any species which lacked the native VHH domain, including the native CDRs and framework regions for a specified VHH antibody. Furthermore, there is no disclosure of any anti-PD-L1 single domain antibody that lacks the specific framework regions for W3156-AP3R2-1A3-z12 and still binds PD-L1.
For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species cannot be achieved by disclosing only one species within the genus. In the instant case, applicant has disclosed a single species of VHH which is not representative of the highly variant genus (any anti-PD-L1 single domain antibody) nor is there disclosure of the common attributes or features (i.e., structural domains) that are essential for activity (binding) or those which are non-essential. See, e.g., Eli Lilly. Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, first paragraph.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states "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). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiefs v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v.Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, the claims do not meet the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Response to Arguments
Applicant asserts at page 10 of the response that the structure of VHH antibodies is well known, that there are more than a hundred papers on VHH antibodies, that they have been crystalized, that humanization methods are known and that there are a large number of sequences of VHH antibodies which have been deposited into public data bases. Applicant also asserts that developing VHHs against a known antigen is routine in the art, usually by immunizing camelid animals. Applicant asserts that generation of both camelid VHHs and humanized VHHs against a known antigen is a routine procedure.
At page 11 of the response, Applicant argues that a person in the art would be familiar with replacing the framework regions in camelid VHHs with human germline sequences to obtain humanized VHHs. Applicant asserts that a “person in the art can expect that with three fixed CDRs, there can be a certain degree of variation in the framework regions without affecting its functionality” and states that a Notice of allowance has been issued in PCT/CN2020/117351. Applicant also noted that two US patents have issued with claims that define the VHH with three CDRs without defining the framework regions.
Applicant’s arguments have been fully considered, but are not found persuasive. Applicant’s arguments regarding the ability of one skilled in the art to be able to generate humanized VHH molecules is not an argument suited for a written description rejection as it is goes to enablement (ability to make and use the claimed invention).
“…the skilled artisan cannot envision the detailed structure of the encompassed genus of antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required.” See Fiefs v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
With regard to the indication of allowable subject matter in the PCT application and other issued US patents, each patent application is examined on its own merits. The Office will not comment on the prosecution of other applications. The instant claims have been rejected for the reasons set forth above and Applicant has not adequately addressed the merits of the rejection.
As pointed out above, the prior art suggests that framework from human and mice immunoglobulins would not be sufficient to provide functionality to camelid antibodies and that VHH domains comprise different structural elements from VH and VL domains which result in a unique and stabilized structure. VHHs are classified into at least four distinct subfamilies which differ from classical VH domains and the prior art demonstrates that even a single amino acid difference in framework can abolish binding activity. The instant specification provides no examples of inserting the claimed CDRs into any generic framework and obtaining a functional VHH nor does the disclosure provide for an antibody that only comprises the 3 CDRs of the isolated VHH. While it might be within the skill of the artisan to generate modified framework or screen libraries to obtain such framework, this is not a written description of the claimed invention. The prior art clearly establishes that 3 defined CDRs alone from a VHH molecule is not sufficient for defining an antigen-binding portion of a VHH because the framework regions of the intact VHH are necessary for such binding. Applicant has not provided evidence to the contrary and therefore, the rejection is maintained for the reasons of record.
Applicant’s arguments at pages 10-12 (including those presented for the written description rejection) are sufficient to overcome the rejection of claims 1-3, 5, 7-10 and 26 for lack of enablement. Applicant’s comments regarding issued patents are not relevant and the Office will not comment on the prosecution of other applications.
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 1 and 26 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 1 recites “wherein the PD-L1 antigen binding moiety is operably linked to the N terminal of the light chain of the VEGF antigen-binding moiety”. However, there is a lack of antecedent basis for “the light chain of the VEGF antigen-binding moiety”. Claim 1 is directed to a bispecific antibody or antigen-binding portion thereof and there is no recitation that the VEGF antigen-binding moiety comprise a light (and a heavy) chain. For example, the VEGF antigen-binding moiety could encompass a single chain antibody which would be a fusion of a heavy chain variable region (comprising the recited CDRs) and a light chain variable region (comprising the recited CDRs) and in this embodiment, there would only be a single chain.
Claim 26 has been amended to recite a “kit comprising a container comprising the bispecific antibody or antigen-binding portion thereof of claim 1”. However, a container cannot comprise an antibody. The container may contain the antibody, but it necessarily would not comprise the antibody unless the antibody is the container, which does not make sense. The claim could be amended to recite that the kit comprises a (1) a container and (2) the bispecific antibody or antigen-binding portion thereof of claim 1. If Applicant would want the antibody/fragment to be contained in the container, the claim could recite that association or include an optional limitation that the antibody/fragment is within the container.
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, 5-, 7-11, 16, 18 and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 8-10, 12, 20 and 22-23 of copending Application No. 17/761,127 (reference application) (allowed on 05 November 2025) in view of U.S. Pat. No. 6,884,879 and WO 2019/168947. Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed bispecific antibody and method of use would be obvious over the claims of ‘127.
‘127 claims a PD-L1 antibody which is identical to the PD-L1 antibody of the bispecific construct of the instant claims. ‘127 claims the PD-L1 binding molecule (a single variable domain VHH) by CDR amino acid sequences (SEQ ID NO:1, 2 and 3) as well as by variable domain (SEQ ID NO:4). The amino acid sequences of the CDRs and variable domain are identical between the instant application and ‘127. ‘127 also claims that the PD-L1 antigen-binding moiety is from a VHH antibody derived from a camelid animal (see claim 8). ‘127 claims pharmaceutical compositions as well as a method of inhibiting or blocking the binding of PD-L1 to PD-1 in a subject as well as treating a PD-L1-expressing cancer. ‘127 does not claim a bispecific antibody comprising the PD-L1 antigen-binding moiety associated with a VEGF antigen-binding moiety or disclose linking the PD-L1 antigen-binding moiety to the N-terminus of the light chain of the VEGF antigen-binding moiety.
WO 2019/168947 teaches and claims a bispecific antibody which comprises a PD-L1 binding domain and a VEGF inhibiting domain (see the claims). ‘947 also teaches pharmaceutical compositions and methods of treating cancer with the bispecific antibody.
The VEGF antigen-binding moiety of the instant claims is the same antibody in U.S. Pat. No. 6,884,879. This antibody is commonly known in the art as bevacizumab.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the PD-L1 antibody of ‘127 with the VEGF antibody of ‘879 to create a bispecific antibody which bound and inhibited both PD-L1 and VEGF because ‘947 teaches a bispecific construct which binds PD-L1 and VEGF and is useful for treating cancer. It further would have been obvious to link the PD-L1 antibody of ‘127 to the N-terminus of the light chain of the VEGF antibody of ‘879 in order to create the bispecific antibody because there are only 4 attachment options (the VEGF antibody is composed of two chains and the PD-L1 antibody is composed of one chain) and any one of the four would have been obvious (the other options are the N-terminus of the heavy chain, the C-terminus of the light chain and the C-terminus of the heavy chain).
One would be motivated to substitute the PD-L1 antibody with the VHH PD-L1 antibody of ‘127 because they both bind to PD-L1 with the expectation that the VHH antibody would function in the same manner. One would also be motivated to substitute the VEGF antibody of ‘879 for the VEGF inhibiting domain (a VEGF receptor peptide) because the antibody of ‘879 binds to VEGF with the expectation that the VEGF antibody would function in the same manner. One would have a reasonable expectation of success in making the substitutions to arrive at the currently claimed bispecific antibody because bispecific antibodies are known in the art and the two components of the bispecific antibody were taught in the art and the motivation to combine them to create a bispecific antibody that binds to both PD-L1 and VEGF is found in ‘786. Therefore, the instant claims are obvious over the claims of ‘127.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues at page 13 of the response that there is no teaching or suggestion in the reference documents (‘127 and ‘879) to combine the PD-L1 antigen binding moiety and the specific VEGF antigen binding moiety let alone how the PD-L1 antigen binding moiety would be linked to the VEGF antigen binding moiety.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The suggestion to combine the anti-PD-L1 VHH of ‘127 with the anti-VEGF antibody of ‘879 comes from the teachings of ‘947 which teaches and claims a bispecific antibody comprising a PD-L1 binding domain and a VEGF inhibiting domain as well as methods of treating cancer with the bispecific antibody.
With regard to how one would link the PD-L1 antigen-binding moiety with the VEGF antigen-binding moiety, the number of options for creating a bispecific antibody (or antigen-binding portion thereof) with the PD-L1 antigen-binding moiety and a VEGF antigen-binding moiety are finite as there are only 4 available points of attachment. The VHH could be attached at the N-terminus of the heavy or light chain of the VEGF antigen-binding moiety or at the C-terminus of the heavy or light chain of the VEGF antigen-binding moiety. Therefore, any such orientation would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Applicant argues that ‘947 discloses a bispecific antibody which comprises a different PD-L1 antigen binding domain and a VEGF inhibiting domain. Applicant argues that there are numerous anti-PD-L1 antibodies and numerous anti-VEGF antibodies known in the art and one cannot easily select the combination of the PD-L1 antigen binding moiety defined and the specific VEGF antigen binding moiety of claim 1. Applicant also argues that ‘947 does not teach or suggest the linkage recited in the claims and asserts “it is difficult for a person in the art to conceive of linking the PD-L1 antigen-binding moiety to the light chain of the VEGF antigen-binding moiety in view of the references”.
Applicant’s arguments have been fully considered but are not found persuasive. Given the teachings of ‘947, one of ordinary skill in the art would have motivation to combine a known PD-L1 antigen-binding moiety (the reference application) with any known VEGF inhibiting domain because ‘947 teach that the combination is useful for treating cancer. One of ordinary skill in the art would have been motivated to select the VEGF antibody of ‘879 because this antibody is bevacizumab and it is one of the most well known and most extensively characterized anti-angiogenetic treatments in the art as evidenced by Garcia et al. (Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treatment Reviews. 86: 102017, 2020). One of ordinary skill in the art would have had a reasonable expectation of success in combining the two antibodies because bispecific antibodies have been known in the art for more than 50 years (see Labrijn et al. Bispecific antibodies: a mechanistic review of the pipeline. Nature Reviews. 18: 585-608, 2019). Lastly, as the options for linking the two antibodies is finite as pointed out above, any of the possible options would have been obvious, including combining the PD-L1 VHH of ‘127 with the VEGF antibody of ‘879 at the N-terminus of the light chain of the VEGF antibody.
Applicant argues at page 14 of the response that the bispecific antibody of the claims achieves an unexpected synergistic technical effect. Applicant points to Example 3.10 in which the effects of W3256 were compared to the combination of anti-VEGF monoclonal antibody (W325-BMK3.uIgG1, bevacizumab) and anti- PD-L1 monoclonal antibody (W315-BMK8.uIgG1K, Atezolizumab), indicating an unexpected synergistic effect may be achieved by the W3256 antibody.
Applicant’s argument has been fully considered, but is not found persuasive. MPEP 716.02(e) makes clear that the comparison which is to be made is with the closest prior art in order to be effective to rebut a prima facie case of obviousness (see In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). The comparison which was made was with a combination of bevacizumab and atezolizumab while the rejection was made over the PD-L1 antibody of reference application ‘127 and bevacizumab, which would be the closest prior art.
Claims 1-3, 7, 16, 18 and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 15 and 17 of copending Application No. 17/784,617 (reference application) in view of U.S. Pat. No. 6,884,879 and WO 2019/168947. Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed bispecific antibody and method of use would be obvious over the claims of ‘617.
‘617 claims a bispecific antibody which comprises a PD-L1 antibody which is identical to the PD-L1 antibody of the bispecific construct of the instant claims. The bispecific antibody of ‘617 binds to both PD-L1 and TGF-beta1. ‘617 claims the PD-L1 binding molecule (a single variable domain VHH) by CDR amino acid sequences (SEQ ID NO:1, 2 and 3) as well as by variable domain (SEQ ID NO:4). The amino acid sequences of the CDRs and variable domain are identical between the instant application and ‘617. ‘617 claims pharmaceutical compositions (claim 15) as well as a method of treating a tumor or inhibiting growth of tumor cells (claim 17). ‘617 does not claim a bispecific antibody comprising the PD-L1 antigen-binding moiety associated with a VEGF antigen-binding moiety.
WO 2019/168947 teaches and claims a bispecific antibody which comprises a PD-L1 binding domain and a VEGF inhibiting domain (see the claims). ‘947 also teaches pharmaceutical compositions and methods of treating cancer with the bispecific antibody.
The VEGF antigen-binding moiety of the instant claims is the same antibody in U.S. Pat. No. 6,884,879. This antibody is commonly known in the art as bevacizumab.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the TGFβ binding domain of ‘617 with the VEGF antibody of ‘879 to create a bispecific antibody which bound and inhibited both PD-L1 and VEGF because ‘947 teaches a bispecific construct which binds PD-L1 and VEGF and is useful for treating cancer. One would be motivated to substitute the TGFβ binding domain of ‘617 with the VEGF antibody of ‘879 because ‘947 teaches that such a construct is useful for treating cancer. It further would have been obvious to link the PD-L1 antibody of ‘917 to the N-terminus of the light chain of the VEGF antibody of ‘879 in order to create the bispecific antibody because there are only 4 attachment options and any one of the four would have been obvious (the other options are the N-terminus of the heavy chain, the C-terminus of the light chain and the C-terminus of the heavy chain). One would have a reasonable expectation of success in making the substitutions to arrive at the currently claimed bispecific antibody because bispecific antibodies are known in the art and the two components of the bispecific antibody were taught in the art and the motivation to combine them to create a bispecific antibody that binds to both PD-L1 and VEGF is found in ‘786. Therefore, the instant claims are obvious over the claims of ‘617.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant argues at pages 14-15 of the response that claim 1 has been amended to recite the specific linkage of the PD-L1 antigen-binding moiety to the VEGF antigen-binding moiety and that “one cannot easily select the combination of the PD-L1 antigen binding moiety defined and the specific VEGF antigen binding moiety of claim 1, from the numerous PD-L1 antibodies and VEGF antibodies already known in the art and that none of the references teach or suggest “the PD-L1 antigen-binding moiety is operably linked to the N terminal of the light chain of the VEGF antigen-binding moiety”.
Applicant’s arguments have been fully considered but are not found persuasive. Given the teachings of ‘947, one of ordinary skill in the art would have motivation to combine a known PD-L1 antigen-binding moiety (the reference application) with any known VEGF inhibiting domain because ‘947 teach that the combination is useful for treating cancer. One of ordinary skill in the art would have been motivated to select the VEGF antibody of ‘879 because this antibody is bevacizumab and it is one of the most well known and most extensively characterized anti-angiogenetic treatments in the art as evidenced by Garcia et al. (Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treatment Reviews. 86: 102017, 2020). One of ordinary skill in the art would have had a reasonable expectation of success in combining the two antibodies because bispecific antibodies have been known in the art for more than 50 years (see Labrijn et al. Bispecific antibodies: a mechanistic review of the pipeline. Nature Reviews. 18: 585-608, 2019). Lastly, as the options for linking the two antibodies is finite as pointed out above, any of the possible options would have been obvious, including combining the PD-L1 VHH of ‘617 with the VEGF antibody of ‘879 at the N-terminus of the light chain of the VEGF antibody.
Applicant again argues that the bispecific antibody as disclosed in the present application has achieved a synergistic technical effect better than the combo group. Applicant’s argument has been fully considered but is not found persuasive. The evidence which Applicant is relying upon has not made a comparison to the closest prior art as the combination data to which Applicant refers did not use the PD-L1 VHH of ‘617, which would be considered the closest prior art.
Claims 1-3, 5, 7-11, 16, 18 and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9, 11, 13, 18, 20, 22 and 28 of copending Application No. 17/763,113 (reference application) in view of U.S. Pat. No. 6,884,879 and WO 2019/168947. Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed bispecific antibody and method of use would be obvious over the claims of ‘113.
‘113 claims a bispecific antibody which comprises a PD-L1 antibody which is identical to the PD-L1 antibody of the bispecific construct of the instant claims. The bispecific antibody of ‘113 binds to both PD-L1 and LAG-3. ‘113 claims the PD-L1 binding molecule (a single variable domain VHH) by CDR amino acid sequences (SEQ ID NO:1, 2 and 3) as well as by variable domain (SEQ ID NO:47). The amino acid sequences of the CDRs and variable domain are identical between the instant application and ‘113. ‘113 claims pharmaceutical compositions (claim 18) as well as a method of modulating an immune response as well as preventing/treating a disease (claims 20 and 22). ‘113 does not claim a bispecific antibody comprising the PD-L1 antigen-binding moiety associated with a VEGF antigen-binding moiety.
WO 2019/168947 teaches and claims a bispecific antibody which comprises a PD-L1 binding domain and a VEGF inhibiting domain (see the claims). ‘947 also teaches pharmaceutical compositions and methods of treating cancer with the bispecific antibody.
The VEGF antigen-binding moiety of the instant claims is the same antibody in U.S. Pat. No. 6,884,879. This antibody is commonly known in the art as bevacizumab.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the LAG-3 binding domain of ‘113 with the VEGF antibody of ‘879 to create a bispecific antibody which bound and inhibited both PD-L1 and VEGF because ‘947 teaches a bispecific construct which binds PD-L1 and VEGF and is useful for treating cancer. One would be motivated to substitute the LAG-3 binding domain of ‘113 with the VEGF antibody of ‘879 because ‘947 teaches that such a construct is useful for treating cancer. It further would have been obvious to link the PD-L1 antibody of ‘113 to the N-terminus of the light chain of the VEGF antibody of ‘879 in order to create the bispecific antibody because there are only 4 attachment options and any one of the four would have been obvious (the other options are the N-terminus of the heavy chain, the C-terminus of the light chain and the C-terminus of the heavy chain). One would have a reasonable expectation of success in making the substitutions to arrive at the currently claimed bispecific antibody because bispecific antibodies are known in the art and the two components of the bispecific antibody were taught in the art and the motivation to combine them to create a bispecific antibody that binds to both PD-L1 and VEGF is found in ‘786. Therefore, the instant claims are obvious over the claims of ‘113.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant asserts at page 15 of the response that the same argument as set forth above (for the previous provisional double patenting rejection) can be applied to this rejection. Applicant’s arguments have been fully considered but are not found persuasive for the reasons provided above (for the previous provisional double patenting rejections).
Claims 1-3, 7-9, 16, and 26-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 106-110, 112-115 of copending Application No. 18/276,394 (reference application) in view of U.S. Pat. No. 6,884,879 and WO 2019/168947. Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed bispecific antibody and method of use would be obvious over the claims of ‘617.
‘394 claims a bispecific antibody which comprises a PD-L1 antibody which is identical to the PD-L1 antibody of the bispecific construct of the instant claims. The bispecific antibody of ‘394 binds to both PD-L1 and TGF-beta1. ‘394 claims the PD-L1 binding molecule (a single variable domain VHH) by CDR amino acid sequences (SEQ ID NO:1, 2 and 3) as well as by variable domain (SEQ ID NO:4). The amino acid sequences of the CDRs and variable domain are identical between the instant application and ‘394. The claims of ‘394 are directed to pharmaceutical compositions. ‘394 does not claim a bispecific antibody comprising the PD-L1 antigen-binding moiety associated with a VEGF antigen-binding moiety.
WO 2019/168947 teaches and claims a bispecific antibody which comprises a PD-L1 binding domain and a VEGF inhibiting domain (see the claims). ‘947 also teaches pharmaceutical compositions and methods of treating cancer with the bispecific antibody.
The VEGF antigen-binding moiety of the instant claims is the same antibody in U.S. Pat. No. 6,884,879. This antibody is commonly known in the art as bevacizumab.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the TGFβ binding domain of ‘394 with the VEGF antibody of ‘879 to create a bispecific antibody which bound and inhibited both PD-L1 and VEGF because ‘947 teaches a bispecific construct which binds PD-L1 and VEGF and is useful for treating cancer. One would be motivated to substitute the TGFβ binding domain of ‘394 with the VEGF antibody of ‘879 because ‘947 teaches that such a construct is useful for treating cancer. It further would have been obvious to link the PD-L1 antibody of ‘394 to the N-terminus of the light chain of the VEGF antibody of ‘879 in order to create the bispecific antibody because there are only 4 attachment options and any one of the four would have been obvious (the other options are the N-terminus of the heavy chain, the C-terminus of the light chain and the C-terminus of the heavy chain). One would have a reasonable expectation of success in making the substitutions to arrive at the currently claimed bispecific antibody because bispecific antibodies are known in the art and the two components of the bispecific antibody were taught in the art and the motivation to combine them to create a bispecific antibody that binds to both PD-L1 and VEGF is found in ‘786. Therefore, the instant claims are obvious over the claims of ‘394
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant asserts at page 15 of the response that the same argument as set forth above (for the previous provisional double patenting rejection) can be applied to this rejection. Applicant’s arguments have been fully considered but are not found persuasive for the reasons provided above (for the previous provisional double patenting rejections).
Conclusion
No claim is allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/Christine J Saoud/Primary Examiner, Art Unit 1645