DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election without traverse of Group I (claims 1-7, 9-11, 13-14, 16 and 17 ) and the species of (i) CTA.03 which comprises the VH of SEQ ID NO: 15 (comprising heavy chain CDRs of SEQ ID NOs: 12-14) and the VL of SEQ ID NO: 20 (comprising light chain CDRs of SEQ ID NOs: 16, 17, and 19), CTA.03 in Fab format comprising the heavy chain of SEQ ID NO: 23 and the light chain of SEQ ID NO: 24, CAT.03 in scFv format: comprising SEQ ID NO: 251, and (ii) CTAT.03 which comprises the VH of SEQ ID NO: 77 (comprising heavy chain CDRs of SEQ ID NOs: 74-76) and the VL of SEQ ID NO: 81 (comprising light chain CDRs of SEQ ID NOs: 78-80), CTAT.03 in scFv format comprising the amino acid sequence of SEQ ID
NO: 258, and CTAT.03 in Fab format comprising a heavy chain of SEQ ID NO: 83 and a
light chain of SEQ ID NO: 84 in the reply filed on 12/23/2025 is acknowledged.
Please note that the variants of CTA.03 mentioned in the response are not examined in this office action.
3. Claims 1-7, 9-11, 13-14, 16-17, 19, 24, 29, 34, 37 and 39 are pending. Claims 8, 12, 15, 18, 20-23, 25-28, 30-33, 35-36 and 38 are canceled. Claims 19, 24, 29, 34, 37 and 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/23/2025.
4. Claims 1-7, 9-11, 13-14, 16 and 17 are under examination.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 12/19/2022, 1/2/2025 and 8/11/2025 have been considered by the examiner.
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:
6. Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825. Specifically sequences present in the specification are not in the sequence listing.
The sequence listing contains 249 sequences. The specification mentions SEQ ID NOs: 254-271, and SEQ ID NOs: 250-253 (see page 3, lines 6 and 17, for example).
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Objections
7. Claim 14 is objected to for reciting “wherein the Fab fragment comprises the first heavy chain and the first light chain” in line 3 (emphasis added).
Claim 14 depends from claim 13. Claim 13 recites “wherein the Fab fragment comprises the second heavy chain, which comprises the second VH and a CH1 fragment, and the second light chain, which comprises the second VL and a light chain constant region.
The word “first” in line 3 of claim 14 should be changed to “second”.
Claim Rejections - 35 USC § 112
8. 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.
9. Claims 7, 10-11 and 14 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.
Claims 7 and 14 are indefinite for reciting SEQ ID NOs: 254-271 and SEQ ID NOs: 250-253, respectively. The sequence listing contains only 249 sequences. The specification does not disclose the actual sequences for SEQ ID NOs: 254-271 and 250-253. Therefore, the metes and bounds of the claimed invention cannot be determined and the claims are indefinite. Claim 10 is rejected because it depends from claim 7 and is indefinite for the same reason as set forth for claim 7.
Claim 11 recites the limitations "the first polypeptide” and “the second polypeptide”. There is insufficient antecedent basis for these limitations in the claim.
Claim Rejections - 35 USC § 112
10. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
11. Claims 6, 7, 9-11, 13-14 and 16-17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 6, 7, 9-11, 13-14 and 16-17 depend or ultimately depend from claim 1. Independent claim 1 requires the first antigen binding fragment to comprise a first heavy chain and a first light chain, and the second antigen binding fragment to comprise a second heavy chain and a second light chain. The specification does not define “a heavy chain” and “a light chain”. A heavy chain is known in the art to comprise a heavy chain variable region (VH) and a heavy chain constant region. A light chain is known in the art to comprise a light chain variable region (VL) and a light chain constant region.
Claims 6, 7, 9-11, 13-14 and 16-17 recite: wherein the first or second antigen binding fragment is a scFv. The specification does not specifically define scFv. An scFv is known in the art to comprise VH-linker-VL or VL-linker-VH, which does not have a constant region. Therefore, claims 6, 7, 9-11, 13-14 and 16-17 do not further limit the subject matter of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112
12. 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.
13. Claims 1, 3-7, 9-11, 13-14 and 16-17 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 drawn to a bi-specific antibody, comprising:
(a) a first antigen binding fragment that binds human CD3, wherein the first antigen binding fragment comprises a first heavy chain comprising a first heavy chain variable region (VH) and a first light chain comprising a first light chain variable region (VL), wherein the first VH comprises the same heavy chain complementary determining regions (CDRs) or no more than 5 amino acid variations relative to a first reference antibody and the first VL comprises the same light chain CDRs or no more than 5 amino acid variations relative to the reference antibody, and wherein the first reference antibody is CTA.02, CTA.03, CTA.04, or CTA.05; and
(b) a second antigen binding fragment that binds a tumor associated antigen (TAA), wherein the second antigen binding fragment comprises a second heavy chain comprising a second heavy chain variable region (VH) and a second light chain comprising a second light chain variable region (VL); wherein:
(a) CTA.02 comprises a VH set forth as SEQ ID NO: 4 and a VL set forth as SEQ ID NO:8;
(b) CTA.03 comprises a VH set forth as SEQ ID NO: 15 and a VL set forth as SEQ IDNO: 20;
(c) CTA.04 comprises a VH set forth as SEQ ID NO: 29 and a VL set forth as SEQ ID NO: 33; and
(d) CTA.05 comprises a VH set forth as SEQ ID NO: 40 and a VL set forth as SEQ ID NO: 44.
Claim 4 further limits claim 1, wherein the second VH comprises the same heavy chain complementary determining regions (CDRs) or no more than five amino acid variations relative to a second reference antibody and the second VL comprises the same light chain CDRs or no more than 5 amino acid variations relative to the second reference antibody, and wherein the second reference antibody is CTAT.01, CTAT.02, CTAT.03, CTAT.04, CTAT.05, CTAT.06, CTAT.07, CTAT.08, CTAT.09, CTAT.10, CTAT.11, CTAT.12, CTAT.13, CTAT.14, CTAT.15, or CTAT.16. ;
wherein:(a) CTAT.03 comprises a VH set forth as SEQ ID NO: 77 and a VL set forth as SEQ IDNO: 81;
(b) CTAT.01 comprises a VH set forth as SEQ ID NO: 51 and a VL set forth as SEQ ID NO: 55;
(c) CTAT.02 comprises a VH set forth as SEQ ID NO: 62 and a VL set forth as SEQ IDNO: 66;
(d) CTAT.04 comprises a VH set forth as SEQ ID NO: 88 and a VL set forth as SEQ ID NO: 92;
(e) CTAT.05 comprises a VH set forth as SEQ ID NO: 99 and a VL set forth as SEQ IDNO: 103;
(f) CTAT.06 comprises a VH set forth as SEQ ID NO: 110 and a VL set forth as SEQ IDNO: 114;
(g) CTAT.07 comprises a VH set forth as SEQ ID NO: 121 and a VL set forth as SEQ IDNO: 125;
(h) CTAT.08 comprises a VH set forth as SEQ ID NO: 132 and a VL set forth as SEQ ID NO: 136;
(i) CTAT.09 comprises a VH set forth as SEQ ID NO: 143 and a VL set forth as SEQ ID NO: 147;
(j) CTAT.10 comprises a VH set forth as SEQ ID NO: 154 and a VL set forth as SEQ IDNO: 158;
(k) CTAT.11 comprises a VH set forth as SEQ ID NO: 165 and a VL set forth as SEQ IDNO: 169;
(l) CTAT.12 comprises a VH set forth as SEQ ID NO: 176 and a VL set forth as SEQ IDNO: 180;
(m) CTAT.13 comprises a VH set forth as SEQ ID NO: 187 and a VL set forth as SEQ IDNO: 191;
(n) CTAT.14 comprises a VH set forth as SEQ ID NO: 198 and a VL set forth as SEQ ID NO: 202;
(o) CTAT.15 comprises a VH set forth as SEQ ID NO: 209 and a VL set forth as SEQ ID NO: 213; and
(p) CTAT.16 comprises a VH set forth as SEQ ID NO: 220 and a VL set forth as SEQ ID NO: 224.
The claims are rejected because the specification does not adequately describe all the species encompass by
(i) the genus of first antigen binding fragments comprising a first VH comprising no more than 5 amino acid variation relative to a first reference antibody, and a first VL comprising no more than 5 amino acid variation relative to a first reference antibody, and
(ii) the genus of second antigen binding fragments comprising a second VH comprising no more than 5 amino acid variation relative to a second reference antibody, and a second VL comprising no more than 5 amino acid variation relative to a second reference antibody.
Please note that claims 7, 10, 11 and 14 are rejected because the recitation of “and/or”.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 (“[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims.”). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Lastly, even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
The limitations “a VH comprising no more than 5 amino acid variation relative to a reference antibody” and “a VL comprising no more than 5 amino acid variation relative to a reference antibody” allow no more than 5 amino acid changes to occur in the CDR regions of the VH and/or VL of a reference antibody. Such changes include substitution, addition and/or deletion. Therefore, the claims encompass a genus of first antigen binding fragments comprising less than 6 CDRs of a reference antibody, and a genus of second antigen binding fragments comprising less than 6 CDRs of a reference antibody.
The specification does not disclose any functional antigen binding fragment that comprises less than 6 CDRs (i.e. heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3) of a reference antibody. There is no evidence in the specification that such antibodies (comprising less than 6 CDRs of a reference antibody) can bind the target to which the reference antibody binds.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (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).
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Herold et al. 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). Murphy et al. (Journal of Immunological Methods, Vol. 463, Pg. 127-133, 2018), teach that altering amino acid D92 in the complementarity determining region light chain region 3 (CDRL3) of single chain fragment variable (scFv) 2G1 obliterates its capacity to bind to microcystin-leucine-arginine (MC-LR)(Page 130, Section 3.2, paragraph 2) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone (Page 131, Column 1, Paragraph 2). The alterations in binding that were observed in these two variants demonstrate the highly influential role of CDRL3 in binding MC-LR. Thus, the state of the art recognized that it would be highly unpredictable that a specific humanized antibody comprising less than all six CDRs of a parental antibody with a desired specificity would retain the antigen-binding function of the parental antibody. Thus, the minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of the parental donor antibody includes six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) from parental donor antibody in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function of the parental donor antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all six CDRs of a parental donor antibody that binds antigen to antibodies that comprise fewer than all six CDRs from the parental donor antibody, wherein the antibodies retain the antigen specificity of the parental donor antibody. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). 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.
That is, the specification provides neither a representative number of the encompassed first antigen binding fragments and second antigen binding fragments comprising less than 6 CDRs of a reference antibody, nor does it provide a descriptive of structural features that are common to the encompassed antigen binding fragments.
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 antibody fragments 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.
Claim Rejections - 35 USC § 112
14. Claims 1, 3-7, 9-11, 13-14 and 16-17 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a first and second antigen binding fragment each comprising all six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) of a reference antibody, does not reasonably provide enablement for a first and second antigen binding fragment each comprising less than 6 CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) of a reference antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CAFC 1988).
Wands states on page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.''
As discussed above in the written description rejection, the claims encompass a genus of first antigen binding fragments which comprise less than 6 CDRs of a reference antibody, and a genus of second antigen binding fragments which comprise less than 6 CDRs of a reference antibody. Please note that claims 7, 10, 11 and 14 are rejected because the recitation of “and/or”.
The breadth of the claims is enormous. The nature of the invention is engineered antibodies where the relative level of skill of those in the art is deemed to be high. The quantity of experimentation is undue in view of breadth of the claims and the unpredictability of the art.
The specification does not provide working examples and guidance on making antigen binding fragments having less than 6 CDRs of a reference antibody and binding to the same target as the reference antibody.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970). While it is understood that the absence of working examples should never be the sole reason for rejecting a claims as being broader than an enabling disclosure, the criticality of working examples in an unpredictable art such as antibody engineering is required for practice of the claimed invention.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (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). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Herold et al. 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). Murphy et al. (Journal of Immunological Methods, Vol. 463, Pg. 127-133, 2018), teach that altering amino acid D92 in the complementarity determining region light chain region 3 (CDRL3) of single chain fragment variable (scFv) 2G1 obliterates its capacity to bind to microcystin-leucine-arginine (MC-LR)(Page 130, Section 3.2, paragraph 2) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone (Page 131, Column 1, Paragraph 2). The alterations in binding that were observed in these two variants demonstrate the highly influential role of CDRL3 in binding MC-LR. Thus, the state of the art recognized that it would be highly unpredictable that a specific humanized antibody comprising less than all six CDRs of a parental antibody with a desired specificity would retain the antigen-binding function of the parental antibody. Thus, the minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of the parental donor antibody includes six CDRs (i.e. VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) from parental donor antibody in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function of the parental donor antibody. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification, limited to antibodies that comprise all six CDRs of a parental donor antibody that binds antigen to antibodies that comprise fewer than all six CDRs from the parental donor antibody, wherein the antibodies retain the antigen specificity of the parental donor antibody. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the cited references, the lack of guidance and direction provided by applicant, and the absence of working examples for making functional antigen binding fragments comprising less than 6 CDRs of a reference antibody, undue experimentation would be required to make/use the claimed invention.
Claim Rejections - 35 USC § 102
15. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
16. Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by
Wu et al. (US 2009/0215992A1, pub. date: 8/27/2009, PTO 892 dated 10/23/2025).
Wu et al. discloses a bispecific antibody comprising a first antigen binding site that binds human CD3 and a second antigen binding site that binds CD20 (a tumor associated antigen), wherein the first antigen (CD3) binding site comprises a VH and a VL of antibody OKT3, the VH comprises SEQ ID NO:100 and the VL comprises SEQ ID NO:104 (Example 4). The amino acid sequences of SEQ ID NOs: 100 and 104 are 100% identical to instant SEQ ID NOs: 4 and 8, respectively, see sequence alignments below:
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17. Claims 1-7, 9-10, 13-14, 16 and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chuang et al. (WO 2018/177371A1, pub. date: Oct 4, 2018, IDS filed on 1/2/2025), as evidenced by applicant’s admission.
Applicant admitted that the instantly claimed antibody CTA.02 scFv/CTAT.03 Fab has been described in WO2018177371, see Example 1 of the instant specification which is reproduced below.
“Two recombinant antibodies, respectively designated as CTA02 scFv/CTAT03 Fab (previously named anti-EGFR Fab/CAT.02 scFv) and CTA01 scFv/CTAT03 Fab (previously named anti-EGFR Fab/aCD3 scFv, have been described in WO2018177371. CTA02scFv/CTAT03Fab and CTA01scFv/CTAT03Fab comprised an anti-EGFR Fab and an anti-CD3 scFv, in which the VH-CH1 and VL-Ck domains of the anti-EGFR Fab respectively had the amino acid sequences of SEQ ID NOs: 83 and 84. The anti-CD3 scFv of the CTA02scFv/CTAT03Fab had the amino acid sequence of SEQ ID NO: 9, and the anti-CD3 scFv of the CTA01scFv/CTAT03Fab is provided in WO2018177371 (CTA01 is the same antibody named as OKT3 in WO2018177371).”
Regarding claims 1-3, Chuang et al. discloses CTA.02 scFv/CTAT.03 Fab. CTA.02 would inherently comprise a VH of instant SEQ ID NO:4 and a VL of instant SEQ ID NO:8.
Regarding claims 4-5, CTAT03 would inherently comprise a VH of instant SEQ ID NO:77 and a VL of instant SEQ ID NO: 81.
Regarding claims 6-7 and 9-10, Chuang et al. teaches a bispecific antibody anti-CD3 Fab/anti-EGFR scFv, wherein the anti-CD3 Fab comprises VHCH1 and VLCK, and the anti-EGFR scFv is linked to CH1 of the anti-CD3 FAB via a peptide linker (Fig. 3(B), [0069], [00129]). CTA.02 would inherently comprise a heavy chain of instant SEQ ID NO:10 and a light chain of instant SEQ ID NO:11.
Regarding claim 13 and 16, Chuang et al. teaches CTA.02 scFv/CTAT.03 Fab. Chuang et al. teaches that in anti-CD3 scFv/anti-EGFR FAB, the anti-CD3 scFv is linked to CH1 of the anti-EGFR FAB via a peptide linker, wherein the peptide linker is at least 5 amino acids in length ([0027], [00129] and Fig. 3(A), [0052]).
Regarding claim 14, CTAT03 would inherently comprise instant SEQ ID NO:83 and SEQ ID NO: 84. Note that the limitation “and/or” is interpreted as “or”.
Regarding claim 17, Chuang et al. teaches anti-EGFR scFv/anti-CD3 scFv (Fig. 3(C)).
A statement by an applicant in the specification or made during prosecution identifying the work of another as "prior art" is an admission which can be relied upon for both anticipation and obviousness determinations, regardless of whether the admitted prior art would otherwise qualify as prior art under the statutory categories of 35 U.S.C. 102. Riverwood Int’l Corp. v. R.A. Jones & Co., 324 F.3d 1346, 1354, 66 USPQ2d 1331, 1337 (Fed. Cir. 2003); Constant v. Advanced Micro-Devices Inc., 848 F.2d 1560, 1570, 7 USPQ2d 1057, 1063 (Fed. Cir. 1988). However, even if labeled as "prior art," the work of the same inventive entity may not be considered prior art against the claims unless it falls under one of the statutory categories. Id.; see also Reading & Bates Construction Co. v. Baker Energy Resources Corp., 748 F.2d 645, 650, 223 USPQ 1168, 1172 (Fed. Cir. 1984) ("[W]here the inventor continues to improve upon his own work product, his foundational work product should not, without a statutory basis, be treated as prior art solely because he admits knowledge of his own work. It is common sense that an inventor, regardless of an admission, has knowledge of his own work.") (MPEP§2129(I)).
Claim Rejections - 35 USC § 103
18. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
19. Claims 1-7, 9-11, 13-14, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Chuang et al. (WO 2018/177371A1, pub. date: Oct 4, 2018, IDS filed on 1/2/2025), in view of Kley et al. (WO 2017/077382A1, pub. date: 5/11/2017) and Cheung et al (US 2017/0210819A1, pub. date: 7/27/2017).
Regarding claims 1-5, Chuang et al. teaches a bispecific antibody (BsAb) comprising a first antigen binding site that binds to CD3 and a second antigen binding site that binds to a tumor antigen, in particular EGFR,
wherein the second antigen (EGFR) binding site is a Fab which comprises a VH-CH1 comprising SEQ ID NO: 76, and a VL-C[Symbol font/0x6B] comprising SEQ ID NO:75, or a scFv which comprises SEQ ID NO: 78,
wherein the first antigen (CD3) binding site is a Fab comprising a VL-C[Symbol font/0x6B] domain and a VH-CH1 domain, or a scFv (Example 1, [0069] and Fig. 3).
The amino acid sequences of SEQ ID NO: 76 and 75 comprise instant SEQ ID NO: 77 and 81, respectively, and are 100% identical to instant SEQ ID NO: 83 and 84 respectively, see sequence alignment below:
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Regarding claims 6, 9 and 10, Chuang et al. teaches a bispecific antibody anti-CD3 Fab/anti-EGFR scFv, wherein the anti-CD3 Fab comprises VHCH1 and VLC[Symbol font/0x6B], and the anti-EGFR scFv is linked to CH1 of the anti-CD3 FAB via a peptide linker (Fig. 3(B), [0069], [00129]).
Regarding claim 13 and 16, Chuang et al. teaches a bispecific antibody anti-CD3 scFv/anti-EGFR FAB, wherein the anti-EGFR Fab comprises VHCH1 and VLC[Symbol font/0x6B], the anti-CD3 scFv is linked to CH1 of the anti-EGFR FAB via a peptide linker, wherein the peptide linker is at least 5 amino acids in length ([00129] and Fig. 3(A), and [0052]).
Regarding claim 14, Chuang et al. teaches a bispecific antibody anti-CD3 scFv/anti-EGFR FAB, wherein the anti-EGFR Fab comprises a VH-CH1 comprising SEQ ID NO: 76, and a VL-C[Symbol font/0x6B] comprising SEQ ID NO:75. The amino acid sequences of SEQ ID NO: 76 and 75 are 100% identical to instant SEQ ID NO: 83 and 84 respectively (see sequence alignment above). Note that the limitation “and/or” is interpreted as “or”.
Regarding claim 17, Chuang et al. teaches a bispecific antibody anti-CD3 scFv/anti-EGFR scFv (Fig. 3 (C)).
Regarding claim 1, Chuang et al. does not teach that the anti-CD3 Fab comprises a VH of instant SEQ ID NO:15, and a VL of instant SEQ ID NO:20.
Regarding claim 7, Chuang et al. does not teach that the anti-CD3 Fab comprises a VHCH1 of instant SEQ ID NO:23, a VLCK of instant SEQ ID NO:24.
Regarding claim 11 (the term “and/or” is interpreted as or), Chuang et al. does not teach that the bispecific antibody comprises instant SEQ ID NO:24.
Regarding claims 1, 7 and 11, Kley et al. teaches a chimeric protein comprising a targeting moiety directed against CD3 expressed on T cells, wherein the targeting moiety is an anti-CD3 antibody, and the anti-CD3 antibody is OKT3 or otelixizumab or fragment thereof (page 68-69). Kley et al. teaches that otelixizumab comprises a heavy chain comprising SEQ ID NO: 195 and a light chain comprising SEQ ID NO: 196 (page 69). The amino acid sequence SEQ ID NO: 195 comprises instant SEQ ID NO: 15 and 23, and the amino acid sequence SEQ ID NO: 196 comprises instant SEQ ID NO: 20 and 24, see sequence alignment below:
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Cheung et al. teaches making bispecific antibody comprising a first antigen binding site that binds to CD3 and as second antigen binding site that binds to a tumor antigen, wherein the first antigen binding site that binds to CD3 comprises a VH and a VL of antibody otelixizumab, mOKT3 or huOKT3 ([0068], [0142] and [0034]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the VH (or VHCH1) and VL (or VLCL) of otelixizumab to make the bispecific anti-CD3/anti-EGFR antibody of Chuang in view of Kley and Cheung. One of ordinary skill in the art would have been motivated to do so because Kley et al. teaches that otelixizumab can be used in making chimeric protein targeting CD3 expressed on T cells and Cheung teaches that otelixizumab can be used to make bispecific antibody comprising a first antigen binding site that binds to CD3 and a second antigen binding site that binds to a tumor antigen. One of ordinary skill in the art would have had a reasonable expectation of success because Kley et al. discloses the sequences of heavy and light chains of otelixizumab and Cheung et al. teaches that otelixizumab can be used to make bispecific antibodies that target T cells and tumor antigens.
Double Patenting
20. 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.
21. Claims 1-7, 9-11, 13-14, 16 and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of copending Application No. 18/682,632 (reference application), in view of Chuang et al. (WO 2018/177371A1, pub. date: Oct 4, 2018, IDS filed on 1/2/2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of copending application disclose a bi-specific antibody specific to CD3 and a tumor associated antigen (TAA), wherein the bi-specific antibody comprises a first antigen binding fragment that binds human CD3, wherein the first antigen binding fragment comprises a first heavy chain that comprises a first heavy chain variable region (VH) and a first light chain that comprises a first light chain variable region (VL) of a first reference antibody, wherein the first heavy chain and the first light chain comprise the same VH and VL as the reference antibody,
wherein the first reference antibody is CTA.02, CTA.03, CTA.04, or CTA.05
wherein the bi- specific antibody comprises a second antigen binding fragment that binds the TAA, which is CD20, CD19, EGFR, HER2, PSMA, CEA, EpCAM, FAP, PD-L1, CD38, CD33, cMET, CD47, TRAIL-R2, mesothelin, or GD2.
The claims of copending application does not disclose that the second antigen EGFR binding fragment comprises instant SEQ ID NOs: 77 and 81, 83 and 84.
The teachings of Chuang et al have been set forth above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the VH and VL of the anti-EGFR antibody of Chuang to make the bispecific anti-CD3/anti-EGFR antibody of the copending application. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Chuang et al. teaches making bispecific anti-CD3/anti-EGFR antibody.
Conclusion
22. No claims are allowed.
23. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1646