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
Status of the Claims
1. Claims 1-9 are the original claims filed 11/6/2023. In the Preliminary Amendment of 2/2/2024, claims 1-9 are canceled and new claims 10-29 are added. Claims 10-29 are the pending claims.
Priority
2. USAN 18/503,113, filed 11/06/2023, is a Continuation of 15/773,167, filed 05/03/2018, now U.S. Patent # 11851488 and having 2 RCE-type filing therein
15/773,167, is a National Stage entry of PCT/US2016/060087, International Filing Date: 11/02/2016, PCT/US2016/060087 Claims Priority from Provisional Application 62/250,451, filed 11/03/2015, PCT/US2016/060087 Claims Priority from Provisional Application 62/267,086, filed 12/14/2015, PCT/US2016/060087 Claims Priority from Provisional Application 62/374,693, filed 08/12/2016.
Information Disclosure Statement
3. As of 7/5/2026, no IDS is on file.
Objections
Specification
4. The disclosure is objected to because of the following informalities:
-) The use of the term ATCC, Tris, Ficoll, chemstation, Zorbax, Xterra, celltiter-glo, FACS, 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
5. Claims 10-29 are objected to because of the following informalities:
-) Claims 10-29 recite “has” and “comprises” in generic claims 10(a) and 19(ii)(a). For consistency with the claim set, “comprising” language is preferred.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claims 10-29 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 pre-AIA the applicant regards as the invention.
-) The claims are indefinite because they fail to provide any frame of reference that would allow one of skill in the art to unambiguously identify the position of any non-natural amino acid much less the residues 114Ala, 115Ser and 129Lys in the heavy chain sequence of claims 10 and 19. Antibody amino acid sequences are not numbered consistently in the art and can be numbered by linear position or using art recognized antibody numbering indexes, for example, Dondelinger et al (Frontiers in Immunology 9(2278): 1-15, 2018; PTO 892) teaches that position can vary depending on the antibody and the numbering system used, e.g., Sequence-based numbering schemes, such as Kabat, EU and IMGT, structure-based numbering schemes such as Chothia, Martin, Gelfand, AbM, AHo. Accordingly, the metes and bounds of the claimed positions cannot be unambiguously construed.
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.
Written Description
7. Claims 10-29 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 interpretation
Claims 10-29 are drawn to a humanized anti-CD3 antibody variant of the SP34 clone that “has” the HC sequence of SEQ ID NO: 3 (VH domain):
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and the HC aa sequence comprises a non-natural amino acid.
It is not clear if the location of the non-natural amino acid falls within all, some or none of the sequence of SEQ ID NO: 3. Claims 11 and 20 identify the non-natural amino acid in the HC with 114Ala, 115Ser and 129Lys, but do not reference whether the substitutions are pertinent to the VH of SEQ ID NO:3. AT least for residues 114 and 115 of SEQ ID NO:3, neither correspond to Ala (A) or Ser (S) but are T and L, respectively. Residue 129Lys is altogether outside the VH sequence of SEQ ID NO:3. The POSA cannot reasonably ascertain whether or what residues in the native sequence of SEQ ID NO: 3 correspond to a non-natural amino acid or to those comprising 114Ala and 115Ser.
The claims are also indefinite because they fail to provide any frame of reference that would allow one of skill in the art to unambiguously identify the position of any non-natural amino acid much less where the substitutions are of 114Ala, 115Ser and 129Lys in the heavy chain sequence as currently written.
“non-natural amino acid”: defined at
[0075] A “non-naturally encoded amino acid” refers to an amino acid that is not one of the 20 common amino acids or pyrolysine or selenocysteine. Other terms that may be used synonymously with the term “non-naturally encoded amino acid” are “non-natural amino acid,” “unnatural amino acid,” “non-naturally-occurring amino acid,” and variously hyphenated and non-hyphenated versions thereof. The term “non-naturally encoded amino acid” also includes, but is not limited to, amino acids that occur by modification (e.g. post-translational modifications) of a naturally encoded amino acid (including but not limited to, the 20 common amino acids or pyrolysine and selenocysteine) but are not themselves naturally incorporated into a growing polypeptide chain by the translation complex. Examples of such non-naturally-occurring amino acids include, but are not limited to, N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine, and O-phosphotyrosine.
Claims 10-29 are drawn to the humanized anti-CD3 antibody that “has” the LC sequence of SEQ ID NO: 6 (VL domain):
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The POSA cannot envision the genus of humanized anti-CD3 antibody variants of the P34 clone of the instant claims comprising any HC variants comprising just any non-natural amino acid at positions 114A, 115S and 129K. The interpretation encompasses a genus of antibody variants beyond those taught in the specification. Because applicant seeks patent protection for all such humanized anti-CD3 antibodies, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Disclosure in the Specification
Claims 10-29 are even more ambiguous based on the selection criteria for the introduction of non-natural amino acids into the anti-CD3 antibody of the invention. Example 1 teaching elements (a)-(j) and that changes to the CDR (j) should not interfere with CD3 binding (a).
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Example 1 provides guidance steps without the specification and drawings as filed that reveal the molecular steps used to obtain the instant claimed anti-CD3 antibodies.
Example 2: does not identify the residue position in the anti-CD3 HC for the introduction of the non-natural amino acid.
Examples 3-4: do not identify the residue position in the anti-CD3 HC for the introduction of the non-natural amino acid.
Example 5: does not identify the residue positions in the anti-CD3 HC for the introduction of the two non-natural amino acids.
Example 6: does not identify the residue position in the anti-CD3 HC for the introduction of the non-natural amino acid.
Example 7: does not identify the residue position in the anti-CD3 HC for the introduction of the non-natural amino acid.
Example 8: does not identify the residue position in the anti-CD3 HC for the introduction of the non-natural amino acid.
Example 9: does not identify the residue position in the anti-CD3 HC for the introduction of the non-natural amino acid.
None of Figures 1-8 identify the residue position in the anti-CD3 HC for the introduction of the non-natural amino acid.
The specification does not describe the molecular methods shown to substitute any one of the specifically recited HC substituted residues with just any non-natural amino acid using the SP34 humanized variant comprising the HC of SEQ ID NO:3 being paired with the SP34 humanized variant comprising the LC of SEQ ID NO: 6, and that retains specific binding for CD3 in a monospecific or bispecific format.
Status of the Art
The specification does not support just an anti-CD3 Fab retaining antigen binding with random incorporation of the non-natural amino acids. Kim et al (J Am Chem Soc. 2012 June 20; 134(24): 9918–9921 (PTO 892)) teaches “pAcPhe was substituted at HC-K138 in the anti-CD3 antibody, UCHT1. This site is distal to the antigen binding site and, when conjugated to the LC-S202 mutant anti-HER2 Fab with the same polyethylene glycol linker used above, should be long and flexible enough to allow the resulting bispecific antibody to productively bind both a CD3 positive T-cell and the HER2 positive target cell simultaneously.”
Even in 2020, antibodies are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even though the protein sequence of CD3 much less the anti-CD3 Sp34 clone was known in the art, this would not have translated into knowledge of the genus of antibodies that could possibly engage it. Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that the specification does not disclose structural features common to the members of the genus for reliably assigning different antibody structures based on insufficient disclosure of the cloning methods for the instant claimed anti-CD3 antibody, which would support the premise that the inventors possessed the full scope of the claimed invention.
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.
8. Claims 10-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11851488. The ref patent is not afforded safe harbor under 35 USC 121 because the instant application is bona fide CON of the parent ref patent.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ref patent claims and the instant claims are drawn to a humanized anti-CD3 antibody variant of the SP34 clone having 100% identity to the HC sequence of SEQ ID NO: 3 (VH domain):
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and the HC aa sequence comprises a non-natural amino acid.
The ref patent claims and the instant claims are drawn to the humanized anti-CD3 antibody of the SP34 clone having 100% identity to the LC sequence of SEQ ID NO: 6 (VL domain):
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The ref patent claims and the instant claims are drawn to the non-natural amino acid substituted for the HC114Ala, HC115Ser and HC129Lys.
The ref patent claims and the instant claims are drawn to the non-natural amino acid being para-acetyl-phenylalanine, para-azido-phenylalanine or p-propargyloxyphenylalanine.
The ref patent claims and the instant claims are drawn to the non-natural amino acid being linked to a biologically active molecule such as folate.
The ref patent claims and the instant claims are drawn to the biologically active molecule, folate, being linked to a water soluble polymer such as a poly(ethylene glycol) moiety.
The ref patent claims and the instant claims are drawn to a bispecific binding molecule, comprising i) a first binding domain that is folate and that specifically binds to a folate receptor, and ii) a second binding domain, the second binding domain comprising identical HC and LC for the monomer of the anti-CD3 antibody. Properties of the bispecific antibody are described herein-above as for the monomer anti-CD3 antibody, and are identical between the ref patent and the instant claims.
Conclusion
9. No claims are allowed.
10. The following reference(s) are pertinent but not effective art to the instant claims:
A) US 20210317213 A1; US 12377294 B2 (Ambrx, Inc.) claims a full anti-CD3 antibody comprising an HC comprising a non-natural amino acid substituted for residues 114A, 115S and 129K and paired with a LC. The HC of the patent claims (SEQ ID NO: 3 or 32) is not the same HC as instant claimed SEQ ID NO:3. Notably, a terminal disclaimer referencing the instant case was not filed in US 12377294.
B) Kularatne et al. (Angew Chem Int Ed Engl 2013 Nov 11;52(46):12101-12104; Epub 2013 Sep 25 (and Supplemental Content: pp1-12)). Kularatne teaches anti-CD3 (UCHT1 clone) Fab-folate conjugate that targets cytotoxic T cells to folate receptor positive (FR+) tumors. The unnatural amino acid pacetylphenylalanine (pAcPhe) was site-specifically incorporated into an anti-CD3 Fab and conjugated to folate via the formation of a stable oxime linkage. Kalarante does not disclose the CD3 humanized VH and VL of SEQ ID NOS: 3 and 6 for SP34 clone nor the residue substitutions but those data in Kalarante shown in Figures 2-3 are identical to Figures 1-2 of the instant application.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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