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 .
Claim Status
Claims 1-19 are pending and under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in claim 10, 12 and the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
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.
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
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.
Specification
The disclosure is objected to because of the following informalities:
1. The misspelling “Miltenyl Company” on Pg. 35 should be corrected to “Miltenyi Biotec”.
2. The use of the term BiTE®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
Claims 6-9 and 5-15 are objected to because of the following informalities:
Regarding claims 6-9, the abbreviation “(BITE)” should be deleted as it refers to a registered trademark (BiTE®, owned by Amgen) and the term bispecific T cell engager is sufficient.
Regarding claims 5-14, the phrase “bispecific T cell engager comprising the sequence of an antibody or antigen-binding fragment targeting CD26” (emphasis added) uses language that is not conventional. It is recommended to delete “the sequence of” so that it reads --bispecific T cell engager comprising an antibody or antigen-binding fragment targeting CD26--.
Regarding claim 15, the following amendment is proposed: --A nucleic acid encoding the antibody or antigen-binding fragment of claim 1.--
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
Claims 10, 12, and 19 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.
Claims 10 and 19 are directed to a Markush grouping of alternatives which should be written as a closed grouping of alternatives and may be set forth as "a material selected from the group consisting of A, B, and C" or "wherein the material is A, B, or C" (MPEP2173.05(h)). In claim 10, the “or” in line 5 should be changed to “and”. In claim 19, “or” should be added before prostate cancer in line 4.
Regarding claim 12, the phrase "such as" 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).
Claim Rejections - 35 USC § 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 2-3, 6-7, and 9 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.
MPEP § 2163 states that 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, 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). 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.
The teachings of the specification and the claimed invention
Claim 1 is directed to an antibody or antigen-binding fragment specifically binding to human CD26 comprising HCDRs set forth in SEQ ID NO: 1-3 and LCDRs set forth in SEQ ID NO: 4, RMS, and SEQ ID NO:5. Dependent claims 2 and 6 claim the antibody can comprise a heavy chain of SEQ ID NO: 6 or 8 and a light chain of SEQ ID NO: 7 or 9, indicating that the heavy chains and light chains are interchangeable to form an antibody that binds human CD26.
The specification teaches clone 18G272 with VH SEQ ID NO: 6 and VL SEQ ID NO: 7 and clone 19G294 with VH SEQ ID NO: 8 and VL SEQ ID NO: 9 (Specification, Pg. 21, [0119]). There is no evidence that the heavy and light chains from the two different clones are interchangeable.
Claim 9 recites that the amino acid sequence of the scFv targeting CD3 is derived from OKT-3, L2K, TR66, UCHT1, SP34, IORT3, Catumaxomab, Blinatumomab, or Solitomab.
The specification does not define the meaning of “derived from”, therefore the term according to its plain meaning broadly encompasses any fragment of the known antibodies and any mutation (deletion, addition, and substitutions) of the known CD3 antibodies, including with the binding regions.
The state of the relevant art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
The prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly 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, the unpredictability of single amino acid changes in an antibody is underscored by Winkler (J Immunol. 2000 Oct 15;165(8):4505-14) who teaches that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (Page 8, Paragraph 1, Line 11).
There are antibodies that bind to a mutated calreticulin known in the art. Stein (Leukemia, 2016 Jan;30(1):131-5) teaches all CALR mutations reported lead to a frameshift generating a new 36 amino-acid C-terminus and generation of a monoclonal antibody (CAL2) to this C-neoterminus by immunizing mice with a representative peptide (abstract). Kralovics (US2015/079091 A1; IDS filed 02/16/2023) teaches a method for diagnosing a myeloid malignancy comprising detecting the presence or absence of one or more mutant alleles in exon 9 of calreticulin (CALR), wherein the presence of one or more mutant alleles indicates a patient has, or is likely to have, a myeloid malignancy (claim 1), as well as calreticulin mutant sequences that comprise SEQ ID NO: 1 in Table 6.
Accordingly, one skilled in the art would be unable to predict or envision a genus of antibodies that bind to CD3 according to the broad claim language. Since the disclosure fails to describe a sufficient number of species to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
Claim analysis
Based on the teachings of the specification and the state of the relevant art, the claims have the following written description issues:
Claims 2 and 6 claim mixing-and-matching of heavy and light chains, wherein the heavy and light chain combinations are not supported in the specification. The specification teaches clone 18G272 with VH SEQ ID NO: 6 and VL SEQ ID NO: 7 and clone 19G294 with VH SEQ ID NO: 8 and VL SEQ ID NO: 9 (Specification, Pg. 21, [0119]).
Claim 9 recites that the amino acid sequence of the CD3-specific scFv is derived from anti-CD3 antibodies that are known in the art, but the term “derived from” broadly reads on fragments that don’t comprise binding regions and mutations in the CDRs of the known antibodies.
Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed antibodies and therefore Applicant was not in possession of the instant claimed invention. See Regents of the University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). Adequate written description of genetic material “'requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention.” Id. 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406. A description of what the genetic material does, rather than of what it is, does not suffice. Id.
In general, absent at least the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally. One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure.
Claims 3 and 7 are dependent on claims 2 and 6, respectively, and do not provide limitations that overcome the written description 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.
Co-pending Application 19/475,335
Claims 1 and 15-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 19/475,335 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patent discloses an antigen binding protein comprising the instantly claimed CDRs. The reference application discloses but does not currently claim the instant heavy and light chains.
Regarding instant claim 1, pertaining to an antibody or antigen-binding fragment specifically binding to human CD26 comprising HCDRs set forth in SEQ ID NO: 1-3 and LCDRs set forth in SEQ ID NO: 4, RMS, and SEQ ID NO:5, ‘335 claim 3 discloses an antigen-binding protein that binds CD26, comprising the same CDRs as the instant invention.
Regarding instant claims 15-17, pertaining to a nucleic acid sequence encoding the amino acid sequence of the antibody or antigen-binding fragment of instant claim 1 (claim 15), a vector comprising the nucleotide sequence (claim 16), and a host cell comprising the vector (claim 17), ‘335 claims 6-8 disclose an isolated nucleic acid encoding the CD26-specific antigen-binding protein, a vector comprising the nucleic acid, and a cell comprising the vector.
Regarding instant claim 18, pertaining to a pharmaceutical composition comprising the antibody or antigen-binding fragment of claim1, ‘335 claim 9 discloses a composition comprising the CD26-specific antigen-binding protein of the disclosure.
Regarding instant claim 19, pertaining to a method for treating a CD26-highly expressing tumor comprising administering to the patient an effective amount of the antibody of claim 1, ‘335 claim 10 discloses a method for treating a disease associated with high-level CD26 comprising administering the CD26-specific antigen-binding protein of the disclosure.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 9-13, and 15-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 19/475,335 as applied to claims 1 and 15-19 above and further in view of Ma (US2018/0155425A1, published 06/07/2018) and Chen (Adv Drug Deliv Rev. 2013 Oct;65(10):1357-69).
Copending Application ‘335 does not teach: (1) a bispecific T cell engager comprising the antibody or antigen-binding fragment targeting CD26 and a CD3 binding region or (2) the instantly claimed sequence of a linker connecting the heavy and light chains of the CD26 scFv.
These deficiencies are taught by Ma and Chen.
Ma:
The disclosure of Ma is directed to a bispecific antibody that specifically binds human CD26 and human CD3 and its use for treating tumors with high CD26 expression (see Abstract).
Regarding instant claim 5, pertaining to a bispecific T cell engager comprising a CD26 scFv with CDRs set forth in claim 1 and a CD3 scFv, Ma claims a bispecific antibody, comprising a variable domain fragment of an antibody that specifically binds to human CD26, and a variable domain fragment of an antibody that specifically binds to human CD3 (Pg. 34, claim 1).
Regarding instant claim 9, wherein the antibody or antigen-binding fragment of claim 5 wherein the amino acid sequence of the scFv targeting CD3 is derived from the disclosed list, Ma teaches the variable domain of the CD3 antibody is derived from anti-CD3 antibodies known in the art such as OKT-3 ([0012], Lines 1-7).
Chen:
The disclosure of Chen is directed to a review of fusion protein linkers known in the art summarizing examples for their design and application (see Abstract).
Regarding instant claims 10-13, pertaining to the linker connecting the variable region of the anti-CD26 scFv, Chen discloses flexible linkers with the (GGGGS)n format, specifically GGGGS and (GGGGS)3 teaching that these flexible linkers provide flexibility and allows for mobility of the connecting functional domains. The (GGGGS)n format allows for length optimization to achieve appropriate separation of functional domains (Pg. 1360, Table 3 and Pg. 1359, 3.1 Flexible linkers, paragraph 1 and 2).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the antibody of ‘335 by (1) formulating as a bispecific T cell engager comprising a known CD3 binding region and (2) connecting the heavy and light chains of the CD26 scFv with a flexible linker known in the art. One would have been motivated to do so because Ma teaches anti-CD26 antibodies can readily be formulated in a bispecific T cell engager for cancer treatment and Chen teaches the linkers GGGGS and (GGGGS)3 provide flexibility in joining heavy and light chains. There would be an expectation of success in modifying the antibody of ‘335 with the teachings of Ma and Chen because Ma and Chen distill to practice the generation of a bispecific T cell engager comprising a CD26 binding domain and the use of well-known flexible linkers.
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
An antibody or antigen-binding fragment comprising HCDR1 SEQ ID NO:1, HCDR2 SEQ ID NO:2, and HCDR3 SEQ ID NO:3, LCDR1 SEQ ID NO:4, LCDR2 consisting of Arg Met Ser, and LCDR3 SEQ ID NO:5 is free of the prior art.
Claims 4, 8, and 14 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROL ANN CHASE whose telephone number is (571)270-0934. The examiner can normally be reached Monday-Friday 9:00am-6:00pm.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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