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 1-113 are the original claims filed 10/26/2023. In the Preliminary Amendment filed 2/21/2024, claims 1-113 are canceled and new claims 114-143 are added. Claims 114-143 are the pending claims.
Priority
2. USAN 18/495,468, filed 10/26/2023, is a Divisional of 16/806,323, filed 03/02/2020, now U.S. Patent # 11839653, 16/806,323 is a Divisional of 15606148, filed 05/26/2017, now U.S. Patent # 10639368, 15/606,148 Claims Priority from Provisional Application 62/420,276, filed 11/10/2016, 15/606,148 Claims Priority from Provisional Application 62/342,610, filed 05/27/2016.
Information Disclosure Statement
3. As of 7/3/2026, a total of six (6) IDS are filed: 10/26/2023; 10/26/2023; 10/21/2024; 7/30/2024; 4/9/2025; and 9/4/2025. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
4. The disclosure is objected to because of the following informalities:
The use of the term, i.e., Liberase, Swiss-prot, GenBank, 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 114-143 are objected to because of the following informalities:
a) Claims 114-143 are objected to for failing to include the full protein name for human TIM-3, e.g., T-cell immunoglobulin and mucin-domain containing-3.
b) Claims 114-143 are objected to because the claims make reference to two different features of the invention, namely, an antibody and a pharmaceutical composition comprising the antibody (MPEP 608.01(n)).
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 119 and 130 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.
a) Claim 119 is drawn to laboratory names for three antibodies: pab1944w and Hum11 (see [0411]) and αHFc-NC-DM1 (see [0441]). The claim is indefinite for failing to recite the corresponding sequence information for the full or partial structure comprising the binding aspect of the antibody that is relevant to the claimed invention.
b) Claim 130 recites the limitation "The method of claim 114, wherein the antibody further comprises a pharmaceutically acceptable carrier or excipient". There is insufficient antecedent basis for this limitation in the claim. Claim 114 is drawn to an antibody or a pharmaceutical composition that comprises the antibody. Claim 130 should properly reference the pharmaceutical composition. Note the objections to the claims herein above for reciting two different features of the invention in the same claim.
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.
7. Claims 120 and 143 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.
a) Claim 120 recites “and/or” language for the presence of a VH of the sequence of SEQ ID NO: 55 and a VL of the sequence of SEQ ID NO: 56. Claim 114 requires both the VH and VL of identical sequences to be present in the anti-hTIM-3 antibody. Claim 102 is broadening from the claim from which it depends.
b) Claim 143 recites the phrase “is derived from a tumor obtained from a subject.” The method claim 114 is drawn to a use in “a subject”. Claim 143 does not discriminate between the subject of the invention of claim 114 and any other subject’s tumor from which the vaccine is derived. Claim 143 is broadening from the claim from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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/ New Matter
8. Claims 114-143 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.
The claimed invention for the anti-TIM-3 VH and VL domains of SEQ ID NOS 55 and 56, respectively, when in view of the VHCDR1-3 and VLCDR1-3 sequences in the dependent claims is inconsistent with what is taught in the table of sequences on pp. 39-40 of the specification.
(A) Instant claimed SEQ ID NO: 55 is a VH consensus sequence:
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415
708
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.
The corresponding claimed HCDR1 sequence (SEQ ID NO: 48) is shown as
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206
448
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, and it does not resemble the sequence string comprising the same X numbering for the VH sequence:
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152
697
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In fact, nowhere do the dependent claims recite X6 and X7 wild card positions and the amino acid preferences thereof. The claimed HCDR2 and HCDR3 of SEQ ID NOS: 2 and 3, respectively, do properly correspond to those domains for the sequence of SED ID NO: 55:
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238
1202
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(B) Instant claimed SEQ ID NO: 56 is a VL consensus sequence:
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524
1188
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The corresponding claimed LCDR1 sequence (SEQ ID NO: 52) is shown as
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109
716
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and it does not resemble the sequence string comprising the same X numbering for the VL sequence:
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534
710
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In fact, nowhere do the dependent claims recite an X3 wild card position and the amino acid preferences thereof. In fact none of the dependent claims recite X4, X5, X6, X7, X8, X9, X10 and X11 wild card positions and the amino acid preferences thereof.
The claimed LCDR2 of SEQ ID NO: 53 does not correspond to the domain for the sequence of SED ID NO: 56.
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109
706
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Again, the X wild card residue numbers do not match what is shown for that sequence stretch in the VL consensus sequence.
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141
715
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The claimed LCDR3 of SEQ ID NO: 54 does not correspond to the domain for the sequence of SED ID NO: 56.
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73
712
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Again, the X wild card residue number does not match what is shown for that sequence stretch in the VL consensus sequence.
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133
708
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The most generic Claim 114 is fatally defective for the for failing to define what the X wild card positions are for each of the VH and VL domains. The dependent claims are fatally defective for failing to correspond in the numbering for the wild card positions in the corresponding VH and VL domains and vice versa. (MPEP 706.03(m) states in part "New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. See MPEP § 608.04 to §608.04(c). See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and MPEP § 2163.05 for guidance in determining whether the addition of specific percentages or compounds after a broader original disclosure constitutes new matter.”)
Written Description
9. Claims 114-143 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.
Here, and inherent to generic Claim 114 are anti-human TIM-3 antibody variants defined by the sequence disclosure as:
SEQ ID NO: 55:
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413
706
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SEQ ID NO: 56
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520
709
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The interpretation encompasses a genus of anti-human TIM-3 antibody variants with amino acid variation falling within frameworks and CDRs, and beyond those taught in the specification. Because applicant seeks patent protection for all such anti- human TIM-3 antibody variants, 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).
Scope of the claimed genus
Thus, the amount of variation for each of the VH and VL domains even while the preferred amino acids are specified, may encompass any number and kind of re-assembled VHCDR1-3 and VLCDR1-3. The percent variation may encompass the presence of non-naturally occurring thiol groups, e.g., methionine, which is potentially disadvantageous because these amino acids can lead to misfolding or mis-conjugation problems.
Here, all of the claims encompass anti-human TIM-3 antibodies, and variations to the VH and VL domains, in which the variable domains, including the complementarity determining regions (CDRs) could vary relative to the VLC and VHC and CDRs found in the parental antibody in addition to the VL frameworks and VH frameworks. The encompassed antibodies are allowed to vary relative to the parental antibody by different combinations of variant CDR1-3 domains no less. The genus encompassed by the claims is therefore very large and there is substantial variation within the genus.
State of the Relevant Art
By the time the invention was made, it was also well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (IDS 10/26/2023) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (IDS 10/26/2023); see also Marchalonis (2003) (IDS 10/26/2023), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, which amino acid substitutions would maintain antigen binding, or which variant VH or VL CDR1-3 could be recombined and maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (IDS 10/26/2023).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (IDS 10/26/2023). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (IDS 10/26/2023)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (IDS 10/26/2023). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies along with recombining VH and VL CDRs1-3, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully discloses antibody clones having VH sequences of SEQ ID NOS: 24-25, VL sequences of SEQ ID NOS: 36-47, heavy chain sequences of SEQ ID NOS: 57-68, and light chain sequences of SEQ ID NO 69.
Are the disclosed species representative of the claimed genus?
It is asserted that the disclosed species are not representative of the claimed genus because the claims encompass amino acid variation in combination with different or rearranged CDR1-3 for both the VH and VL chains. The genus of all possible anti-human TIM-3 antibodies encompassed by the most generic claims would be structurally distinct but unpredictable whether the structure/function correlation was met for binding to human TIM-3. The specification does not identify which all of which VH and VL CDR combinations much less those comprising variation, are essential for the recited function of binding human TIM-3. Neither the specification nor the prior art provides guidance as to what structural changes can be made to the parent sequences and still predictably arrive at an antibody that binds human TIM-3. The disclosed species therefore do not represent the claimed genus.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional variants much less recombined as between different CDR1, CDR2 and CDR3 variants within any given VH or VL domain.
Even in 2021, therapeutic 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 (IDS 10/26/2023)) 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 (IDS 10/26/2023)), 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 human TIM-3 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 (IDS 10/26/2023)). 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 (IDS 10/26/2023)) (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 neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus for reliably assigning different antibody structures based on sequence data for the full contextual structures for the sequences of SEQ ID NOS: 55 and 56, 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
10. Claims 114-143 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 32 of U.S. Patent No. 10,639,368.
The original grounds for restriction (OA, 9/19/2018; USAN 15/606,148; USPN 10,639,368) identified a pharmaceutical composition comprising the antibody of Group I and a method of increasing T cell activation with the antibody or pharmaceutical composition of claim 1 of Group VII. Accordingly, the pharmaceutical composition is the linking aspect between Groups I and VII.
Although the claims at issue are not identical, they are not patentably distinct from each other because Ref claims 32 and 1 teach an antibody and a pharmaceutical composition comprising the same species of antibodies that fall within the meaning of instant VH of SEQ ID NO: 55 and instant VL of SEQ ID NO: 56 corresponding to instant claims 116-117:
Ref 32. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or excipient.
Ref 1. An isolated antibody that specifically binds to human TIM-3, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2 and CDRH3 and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 14, 21, and 22; 4, 2, 3, 14, 21, and 22; 5, 2, 3, 14, 21, and 22; 6, 2, 3, 14, 21, and 22; 7, 2, 3, 14, 21, and 22; 8, 2, 3, 14, 21, and 22; 9, 2, 3, 14, 21, and 22; 10, 2, 3, 14, 21, and 22; 11, 2, 3, 14, 21, and 22; 12, 2, 3, 14, 21, and 22; or 1, 2, 3, 15, 18, and 22, respectively.
11. Claims 114-143 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 10912828. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims 114-143 are drawn to the same subject matter for the anti-TIM-3 antibodies and overlapping subject matter for the anti-TIM-3 antibodies comprising the VH and VL sequences of SEQ ID NOS 55 and 56 as instantly claimed.
Ref claims overlapping with VH and VL sequences from instant claims 116-117 and 122-123 for antibodies and pharmaceutical compositions thereof:
1. An isolated antibody that specifically binds to human TIM-3, comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences of SEQ ID NOs: 5, 2, and 3, respectively; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 46.
2. The isolated antibody of claim 1, wherein the amino acid sequence of the light chain variable region consists of the amino acid sequence of SEQ ID NO: 46.
3. The isolated antibody of claim 1, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 69.
4. The isolated antibody of claim 3, wherein the amino acid sequence of the light chain consists of the amino acid sequence of SEQ ID NO: 69.
5. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or excipient.
6. A pharmaceutical composition comprising the antibody of claim 2 and a pharmaceutically acceptable carrier or excipient.
7. A pharmaceutical composition comprising the antibody of claim 3 and a pharmaceutically acceptable carrier or excipient.
8. A pharmaceutical composition comprising the antibody of claim 4 and a pharmaceutically acceptable carrier or excipient.
9. An isolated antibody that specifically binds to human TIM-3, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28; and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences of SEQ ID NOs: 14, 21, and 22, respectively.
10. The isolated antibody of claim 9, wherein the amino acid sequence of the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 28.
11. The isolated antibody of claim 9, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 61.
12. The isolated antibody of claim 11, wherein the amino acid sequence of the heavy chain consists of the amino acid sequence of SEQ ID NO: 61.
13. A pharmaceutical composition comprising the antibody of claim 9 and a pharmaceutically acceptable carrier or excipient.
14. A pharmaceutical composition comprising the antibody of claim 10 and a pharmaceutically acceptable carrier or excipient.
15. A pharmaceutical composition comprising the antibody of claim 11 and a pharmaceutically acceptable carrier or excipient.
16. A pharmaceutical composition comprising the antibody of claim 12 and a pharmaceutically acceptable carrier or excipient.
17. An isolated antibody that specifically binds to human TIM-3, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 46.
18. The isolated antibody of claim 17, wherein the amino acid sequence of the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 28; and the amino acid sequence of the light chain variable region consists of the amino acid sequence of SEQ ID NO: 46.
19. The isolated antibody of claim 17, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 61.
20. The isolated antibody of claim 19, wherein the amino acid sequence of the heavy chain consists of the amino acid sequence of SEQ ID NO: 61.
21. The isolated antibody of claim 17, wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 69.
22. The isolated antibody of claim 21, wherein the amino acid sequence of the light chain consists of the amino acid sequence of SEQ ID NO: 69.
23. A pharmaceutical composition comprising the antibody of claim 17 and a pharmaceutically acceptable carrier or excipient.
24. A pharmaceutical composition comprising the antibody of claim 18 and a pharmaceutically acceptable carrier or excipient.
25. A pharmaceutical composition comprising the antibody of claim 19 and a pharmaceutically acceptable carrier or excipient.
26. A pharmaceutical composition comprising the antibody of claim 20 and a pharmaceutically acceptable carrier or excipient.
27. A pharmaceutical composition comprising the antibody of claim 21 and a pharmaceutically acceptable carrier or excipient.
28. A pharmaceutical composition comprising the antibody of claim 22 and a pharmaceutically acceptable carrier or excipient.
29. An isolated antibody that specifically binds to human TIM-3, comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 61; and the light chain comprises the amino acid sequence of SEQ ID NO: 69.
30. The isolated antibody of claim 29, wherein the amino acid sequence of the heavy chain consists of the amino acid sequence of SEQ ID NO: 61.
31. The isolated antibody of claim 29, wherein the amino acid sequence of the light chain consists of the amino acid sequence of SEQ ID NO: 69.
32. The isolated antibody of claim 29, wherein the amino acid sequence of the heavy chain consists of the amino acid sequence of SEQ ID NO: 61, and the amino acid sequence of the light chain consists of the amino acid sequence of SEQ ID NO: 69.
33. A pharmaceutical composition comprising the antibody of claim 29 and a pharmaceutically acceptable carrier or excipient.
34. A pharmaceutical composition comprising the antibody of claim 30 and a pharmaceutically acceptable carrier or excipient.
35. A pharmaceutical composition comprising the antibody of claim 31 and a pharmaceutically acceptable carrier or excipient.
36. A pharmaceutical composition comprising the antibody of claim 32 and a pharmaceutically acceptable carrier or excipient.
12. Claim 114-143 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 12011481. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims 114-143 are drawn to the same subject matter for the anti-TIM-3 antibodies and overlapping subject matter for the anti-TIM-3 antibodies comprising the VH and VL sequences of SEQ ID NOS 55 and 56 as instantly claimed.
Ref claims overlapping with VH and VL sequences from instant claims 116-117 and 122-123 for antibodies and pharmaceutical compositions thereof:
1. An isolated antibody that specifically binds to human T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) comprising a heavy chain variable region (VH) comprising complementarity determining regions CDRH1, CDRH2, and CDRH3 and a light chain variable region (VL) comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein the VH comprises the CDRH1, CDRH2, and CDRH3 of an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, and 26 and the VL comprises the CDRL1, CDRL2, and CDRL3 of an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 39, 40, 41, 44, and 47.
2. The isolated antibody of claim 1, wherein the CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively.
3. The isolated antibody of claim 1, wherein the CDRL1, CDRL2, and CDRL3 comprise amino acid sequences selected from the group consisting of SEQ ID NOs: 14, 20, and 22; 14, 17, and 22; 14, 17, and 23; 14, 19, and 22; and 16, 20, and 22, respectively.
4. The isolated antibody of claim 1, wherein the CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively, and the CDRL1, CDRL2, and CDRL3 comprise amino acid sequences selected from the group consisting of SEQ ID NOs: 14, 20, and 22; 14, 17, and 22; 14, 17, and 23; 14, 19, and 22; and 16, 20, and 22, respectively.
5. The isolated antibody of claim 1, wherein the VH comprises an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, and 26.
6. The isolated antibody of claim 1, wherein the VH comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, and 26.
7. The isolated antibody of claim 1, wherein the VL comprises an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 39, 40, 41, 44, and 47.
8. The isolated antibody of claim 1, wherein the VL comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 39, 40, 41, 44, and 47.
9. The isolated antibody of claim 1, wherein the VH comprises an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, and 26, and the VL comprises an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 39, 40, 41, 44, and 47.
10. The isolated antibody of claim 1, wherein the VH comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, and 26, and the VL comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 37, 39, 40, 41, 44, and 47.
11. The isolated antibody of claim 1, wherein the VH and VL comprise amino acid sequences at least 95% identical to the amino acid sequences of SEQ ID NOs: 26 and 41, 24 and 41, 25 and 39, 24 and 47, 25 and 40, 26 and 47, 25 and 37, 25 and 44, 25 and 41, or 25 and 47, respectively.
12. The isolated antibody of claim 1, wherein the VH and VL comprise the amino acid sequences of SEQ ID NOs: 26 and 41, 24 and 41, 25 and 39, 24 and 47, 25 and 40, 26 and 47, 25 and 37, 25 and 44, 25 and 41, or 25 and 47, respectively.
13. The isolated antibody of claim 1, wherein the antibody comprises a heavy chain constant region selected from the group consisting of a wild type human IgG.sub.1, IgG.sub.2, IgG.sub.3, IgG.sub.4, IgA.sub.1, and IgA.sub.2, or a variant thereof.
14. The isolated antibody of claim 13, wherein the heavy chain constant region is selected from the group consisting of: (a) the variant of the wild type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to a human Fc gamma receptor with lower affinity than the wild type human IgG heavy chain constant region binds to the human Fc gamma receptor, optionally wherein the human Fc gamma receptor is selected from the group consisting of FcγRI, FcγRII, and FcγRIII; (b) IgG.sub.1 comprising an N297A mutation, numbered according to the EU numbering system; (c) IgG.sub.1 comprising an N297Q mutation, numbered according to the EU numbering system; (d) non-fucosylated IgG.sub.1; and (e) IgG.sub.4 comprising an S228P mutation.
15. The isolated antibody of claim 13, wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 71, 72, 73, 74, and 75.
16. The isolated antibody of claim 1, wherein the antibody comprises a light chain constant region selected from the group consisting of human kappa light chain and human lambda light chain.
17. The isolated antibody of claim 16, wherein the light chain constant region comprises the amino acid sequence of SEQ ID NO: 76 or 77.
18. The isolated antibody of claim 12, wherein the antibody comprises a heavy chain constant region selected from the group consisting of a wild type human IgG.sub.1, IgG.sub.2, IgG.sub.3, IgG.sub.4, IgA.sub.1, and IgA.sub.2, or a variant thereof.
19. The isolated antibody of claim 18, wherein the heavy chain constant region is selected from the group consisting of: (a) the variant of the wild type human IgG heavy chain constant region, wherein the variant human IgG heavy chain constant region binds to a human Fc gamma receptor with lower affinity than the wild type human IgG heavy chain constant region binds to the human Fc gamma receptor, optionally wherein the human Fc gamma receptor is selected from the group consisting of FcγRI, FcγRII, and FcγRIII; (b) IgG.sub.1 comprising an N297A mutation, numbered according to the EU numbering system; (c) IgG.sub.1 comprising an N297Q mutation, numbered according to the EU numbering system; (d) non-fucosylated IgG.sub.1; and (e) IgG.sub.4 comprising an S228P mutation.
20. The isolated antibody of claim 18, wherein the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 70, 71, 72, 73, 74, and 75.
21. The isolated antibody of claim 12, wherein the antibody comprises a light chain constant region selected from the group consisting of human kappa light chain and human lambda light chain.
22. The isolated antibody of claim 21, wherein the light chain constant region comprises the amino acid sequence of SEQ ID NO: 76 or 77.
23. A polypeptide comprising a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: [37,] 39, 40, 41, 44, and 47.
24. The polypeptide of claim 23, wherein the polypeptide is an antibody light chain.
25. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or excipient.
26. A polypeptide comprising a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 25, and 26.
27. The polypeptide of claim 26, wherein the polypeptide is an antibody heavy chain.
28. The polypeptide of claim 27, wherein the amino acid sequence of the polypeptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 57, 58, and 59.
Conclusion
13. No claims are allowed.
14. 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 ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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