DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 13 is objected to because of the following informalities: line 2 appears to recite “claim – 12”. Examiner suggests deleting the hyphen. Appropriate correction is required.
Claim 26 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 8-25, and 27-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
Claim 1. An isolated monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having the polypeptide sequences of:
(1) SEQ ID NOs: 1, 48, 49, 50, 51, and 6, respectively;
(2) SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively;
(3) SEQ ID NOs: 13, 2, 14, 4, 28, and 6, respectively;
(4) SEQ ID NOs: 13, 2, 15, 4, 5, and 6, respectively;
(5) SEQ ID NOs: 16, 17, 18, 29, 30, and 6, respectively;
(6) SEQ ID NOs: 19, 20, 21, 4, 5, and 6, respectively;
(7) SEQ ID NOs: 22, 23, 24, 31, 5, and 32, respectively;
(8) SEQ ID NOs: 25, 26, 27, 33, 34, and 35, respectively;
(9) SEQ ID NOs: 1, 2, 49, 4, 5, and 6, respectively; or
(10) SEQ ID NOs: 1, 2, 49, 50, 51, and 6, respectively;
wherein the antibody or antigen-binding fragment thereof specifically binds chemokine (C-C motif) receptor 8 (CCR8).
and
Claim 25. An isolated monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having the polypeptide sequences of SEQ ID NOs: 1, 48, 49, 50, 51, and 6, respectively.
and
Claim 27. An isolated monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain variable region having a polypeptide sequence at least 95% identical to SEQ ID NO: 9 and a light chain variable region having a polypeptide sequence at least 95% identical to SEQ ID NO: 10 and comprising a HCCDR1, HCCDR2, HCCDR3, LCCDR1, LCCDR2, and LCCDR3 having the polypeptide sequences of:
SEQ ID NOs: 1, 48, 49, 50, 51, and 6, respectively,
SEQ ID NOs: 1, 2, 49, 4, 5, and 6, respectively,
SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively, or
SEQ ID NOs: 1, 2, 49, 50, 51, and 6, respectively.
does not reasonably provide enablement for:
Claim 1. An isolated monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having a polypeptide sequences of:
(1) SEQ ID NOs: 1, 48, 49, 50, 51, and 6, respectively;
(2) SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively;
(3) SEQ ID NOs: 13, 2, 14, 4, 28, and 6, respectively;
(4) SEQ ID NOs: 13, 2, 15, 4, 5, and 6, respectively;
(5) SEQ ID NOs: 16, 17, 18, 29, 30, and 6, respectively;
(6) SEQ ID NOs: 19, 20, 21, 4, 5, and 6, respectively;
(7) SEQ ID NOs: 22, 23, 24, 31, 5, and 32, respectively;
(8) SEQ ID NOs: 25, 26, 27, 33, 34, and 35, respectively;
(9) SEQ ID NOs: 1, 2, 49, 4, 5, and 6, respectively; or
(10) SEQ ID NOs: 1, 2, 49, 50, 51, and 6, respectively;
wherein the antibody or antigen-binding fragment thereof specifically binds chemokine (C-C motif) receptor 8 (CCR8). – wherein only one of the CDR sequences are required
nor
Claim 25. An isolated monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, a light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3, having a polypeptide sequences of SEQ ID NOs: 1, 48, 49, 50, 51, and 6, respectively. – wherein only one of the CDR sequences are required
nor
Claim 27. An isolated monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain variable region having a polypeptide sequence at least 95% identical to SEQ ID NO: 9 and a light chain variable region having a polypeptide sequence at least 95% identical to SEQ ID NO: 10. – without recitation of the CDRs.
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 use the invention commensurate in scope with these claims.
Claims 1 and 25 are indefinite and interpreted as reciting anti-CCR8 antibodies comprising a HCCDR1, HCCDR2, HCCDR3, LCCDR1, LCCDR2, and LCCDR3 and only a single CDR comprising a recited SEQ ID NO. Thus, the claims encompass several genera of antibody comprising merely one of the recited sequences and having the function of binding CCR8. For example, claim 1 recites 33 different SEQ ID NOs and, thus, encompasses 33 different genera of anti-CCR8 antibodies. Thus, claims 1 and 25 encompass an enormous breadth of antibodies wherein only the structure of a single CDR and their function of binding CCR8 are defined. Claims 2, 8-24, and 28-34 depend from claims 1 or 25 and fail to define a set of six CDRs.
Claim 27 recites an antibody or fragment thereof without recitation of the target antigen. The instant disclosure states that “[i]n general, antibodies are proteins or peptide chains that exhibit binding specificity to a specific antigen”; see paragraph 0073. The instant disclosure teaches antibodies comprising VH and VL sequences having 95% identity to SEQ ID NOs: 9 and 10, and these antibodies are humanized and function to bind CCR8; see Example 8. Given that the instant disclosure teaches that antibodies exhibit binding specificities to specific antigens, the limitation “isolated monoclonal antibody or antigen-binding fragment thereof” impacts the implicit function of binding a specific antigen. The only target antigen taught in the instant disclosure is CCR8.
It is well known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, 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. 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 parent 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.
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 Rudikoff et al. (PNAS. 79: 1979-1983; Published: March 15, 1982). Rudikoff et al. teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
MacCallum et al. (Journal of Molecular Biology. 262(5): 732-745; Published: October 11, 1996) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations; see page 733 right column and page 735 left column.
De Pascalis et al. (The Journal of Immunology. 169(6): 3076-3084; Published: September 15, 2002) demonstrated that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site; see page 3079 right column. Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs; see page 3080 left column.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (BBRC 2003, 307(1): 198-205; Published: July 18, 2003), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs. Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3; see page 199 left column and page 202 left column.
Further, Chen et al. (Journal of Molecular Biology. 293: 865-881; Published: November 5, 1999) describes high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3; see page 8660.
While Chen et al. highlights the significance of the heavy chain CDRs to antigen binding, Padlan et al. (PNAS. 86: 5938-5942; Published: August 1, 1989) describes the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen.
Finally, Lamminmaki et al. (Journal of Biological Chemistry. 276(39): 36687-36694; Published: September 28, 2001) describes the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen - even CDR2 of VL, which is rarely directly involved in hapten binding.
Similarly, 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 Murphy et al. (Journal of Immunological Methods. 463: 127-133; Published: October 12, 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 microcystinleucine-arginine (MC-LR) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone; see page 130, Section 3.2, paragraph 2 and 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.
The art recognizes the significance of all six CDRs to antibody specificity. However, the instant claimed antibodies of claims 1 and 25 require merely one of the recited CDR sequences and the specificity of CCR8 binding. Additionally, the instantly claimed antibody or fragment thereof of claim 27 encompasses embodiments where the 5% variability in identity occurs in these CDRs which are critical to antigen binding function.
Further, there is no known prior art structure function relationship for an antibody comprising only one of the recited CDR sequences and binding CCR8 nor for an antibody comprising a VH of SEQ ID NO: 9 and a VL of SEQ ID NO: 10 that would allow a one of ordinary skill in the art to predictably vary the CDR regions and obtain an antibody that binds an epitope of CCR8. Moreover, it is unpredictable to what target the antibody or fragment thereof with up to 5% variability relative to each of SEQ ID NOs: 9 and 10, wherein the variability occurs within the CDRs, would bind.
The amount of experimentation required to make and use an antibody which comprises only one defined CDR sequence and has the function of binding CCR8 is enormous. The amount of experimentation that would be required for the skilled artisan to probe such an enormous sequence space to determine which antibodies will have the functional activities recited in claims 1 and 25 amounts to undue trial and error experimentation. Moreover, there is a level of unpredictability in the art associated with making single versus multiple changes to any given CDR. For example, even in those instances where one can show certain residues of a given CDR are generally tolerant of single amino acid changes, this does not necessarily mean a combination of single amino acid changes, even to the same residues shown to tolerate change when mutated in isolation, will be tolerated. As an example, Brown et al. (Journal of Immunology. 156(9):3285-91; Published: May 1, 1996) describes how the VH CDR2 in a particular antibody was generally tolerant of single amino acid changes; however, the antibody lost binding upon the introduction of pairs of single amino changes in the same region; see, in particular Tables I and II and column bridging paragraph on page 3290.
Similarly, the amount of experimentation to make and use an antibody or antigen-binding fragment having at least 95% identity to the VH and VL of SEQ ID NOs: 9 and 10 is enormous. The number of possible variants having at least 95% identity to the VH and VL of SEQ ID NOs: 9 and 10 is immense. Additionally, because antibodies have the implicit function of binding a specific antigen, in order for the claimed antibodies to have utility, one would further have to screen each variant to identify the target antigen.
Considering the unpredictability, the high level of skill, and the breath scope encompassed in claims 1, 2, 8-25, and 27-34, it would take more than reasonable experimentation to make and use the invention commensurate in scope with the claims.
Claims 16-19 and 29-32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
“treating” cancer in a subject, wherein “treating” refers to:
“an amelioration or reversal of at least one measurable physical parameter related to a cancer”,
“causing regression, preventing the progression, or at least slowing down the progression of the [cancer]”,
“an alleviation, or reduction in the duration of one or more symptoms associated with the [cancer]”,
“prevention of the recurrence of the [cancer]”,
“an increase in the survival of a subject having the [cancer]”, and/or
“elimination of the [cancer]”
does not reasonably provide enablement for:
“treating” cancer in a subject, wherein “treating” refers to: “prevention of the development or onset”.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claims 16-19 and 29-32 encompass the treatment of any cancer by administering the pharmaceutical composition comprising the antibody or antigen-binding domain of claim 1 or 10 or the bispecific antibody of claim 10. The limitation “treating” in claims 16 and 29 encompasses the “prevention of the development or onset” of cancer; see paragraph 00143 for the definition of “treating”. In other words, the claims encompass methods for preventing cancer.
While the level of ordinary skill in the art is high, the level of unpredictability in the art is also high. Cancer development is understood to begin with genetic alteration and the resulting promotion and progression resulting in karyotypic instability and malignant growth; see Pitot et al. (Cancer. 73(3): 962-970; Published: August 1, 1993). The initiation, promotion, and progression of this genetic instability is multifactorial and can be brought about by a plethora of chemical, physical, or biologic carcinogens; see Pitot et al. Following the development of a single malignant cell, several enabling characteristics or hallmarks, including sustained proliferative signaling, avoidance of apoptosis, and immune evasion, further the progression of cancer; see Hanahan et al. (Cell. 144(5): 646-674; Published: March 4, 2011). While there exist several models for introducing genetic instability, there is currently no animal model to recapitulate the transition from immune surveillance to immune evasion and escape.
The nature of carcinogenesis clearly lies in genetic instability and, thus, a mode of cancer prevention should aim to reverse genetic instability. Yet, the nature of this invention aims to aleivate the immunosuppressive tumor microenvironment that enables immune evasion by targeting CCR8+ Tregs – thereby addressing enabling characteristics or hallmarks of cancer, but not the initiation itself.
Applicant has demonstrated the anti-tumor efficacy of treating C57BL/6 mice implanted with MC38 colon cancer cells, the ex-vivo Treg depletion in renal cell carcinoma samples; see Examples 14 and 15, and 16 and 18, respectively. However, Applicant has not demonstrated the claimed pharmaceutical compositions efficacy in preventing the development or onset of cancer. Nor has Applicant provided any guidance regarding preventative treatment, including preventative dosing regimens, how to identify a subject how would benefit from preventative treatment, or when to initiate preventative treatment.
The amount of experimentation to required to formulate such guidance would be enormous. One would have to demonstrate the efficacy of the combination or composition in several models inducing genetic instability across several different types of cancers and determine the appropriate regimen (doses and frequency) for use of the combination or composition in a preventative setting. Further, one would have to conduct population analysis to identify definitive characteristics which indicate that a subject is at risk of developing any cancer to a degree that would outweigh potential adverse effects of treatment with the claimed combination or composition.
Thus, considering the high level of skill in the art, the state of the art, the level of predictability, and the guidance and examples provided, the experimentation required to enable the full scope of the claimed invention would not be reasonable.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 8-24, and 28-34 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.
Regarding claims 1 and 25, the claims recite “having a polypeptide sequences of SEQ ID NOs: […]”. Having is defined in paragraph 0049 of the disclosure as “non-exclusive or open-ended”. Thus, is interpreted synonymous to comprising. The indefiniteness arises from the limitation “a polypeptide sequences”. Specifically, “a” indicates the singular of the noun to which it precedes, while “sequences” indicates the plural. It is unclear whether the antibody or fragment thereof is required to have/comprise merely “a” singular sequence of those recited or all of the “sequences” recited.
For the purpose of compact prosecution, claims 1 and 25 are interpreted as reciting an antibody or fragment thereof which comprises only one of the sequences recited.
Examiner suggests amending “a polypeptide sequences of” to “the polypeptide sequences of” to potentially overcome the 112(a), 112(b), and 102 rejections. It is understood in the art that antibody CDRs comprise polypeptide sequences. The earlier recitation of the antibody or fragments thereof comprising a set of six CDRs provides sufficient antecedent basis for “the polypeptide sequences of”.
Claims 2, 8-24, and 28-34 are rejected for depending from claims 1 or 25 and failing to remedy the indefiniteness.
Further, claim 1 recites “preferably human CCR8” in the final line. This limitation makes unclear whether binding human CCR8 is required and whether the claim excludes antibodies which binds CCR8 or other species.
For the purpose of compact prosecution, claim 1 is interpreted as reciting the antibody or fragment thereof binds CCR8. Examiner suggests amending to reflect binding to CCR8 – not that of a specific species – as claim 9 recites binding cynomolgus CCR8 and amending to a specific species could create potential 112d issues with claim 9.
Claims 2, 3, 8-24, and 28-34 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
Similarly, claims 17 and 30 recite “preferably”, “more preferably”, and “most preferably”. It is unclear whether or not the limitations that follow preferably are required.
For the purpose of compact prosecution, claims 17 and 30 are interpreted as requiring that the cancer is a solid tumor.
Claim Rejections - 35 USC § 112(d)
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.
Claims 8 and 10 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.
Claim 8 recites that the monoclonal antibody or antigen-binding fragment has capabilities, none of which further limit the structure recited in claim 1. For example, “mediating recruitment of conjugated drugs” in claim 8 does not require the antibody or antigen-binding fragment of claim 1 conjugated to a drug. Merely, that the antibody or antigen-binding fragment of claim 1 is “capable” of performing this function which is inherent to the structure of claim 1. Thus, claim 8 fails to further limit the product of claim 1.
Claim 10 recites “A bispecific antibody or antigen-binding fragment thereof comprising the monoclonal antibody or antigen-binding fragment thereof of claim 1.” Bispecific antibody is defined in paragraph 0082 of the instant disclosure and encompasses bispecific antibodies comprising antigen-binding fragments. The recitation of “antigen-binding fragment thereof” in the alternative in combination with “comprising the […] antigen-binding fragment thereof of claim 1” in the absence of recitation of comprising a second antigen-binding site reads on claim 1. In other words, an antigen-binding fragment of claim 1, for example an scFv comprising SEQ ID NOs: 1, 48, 49, 50, 51, and 6, reads on both claims 1 and 10 because claim 10 does not require a bispecific antibody nor a second antigen-binding fragment. Thus, claim 10 fails to further limit claim 1.
Examiner suggests deleting “or antigen-binding fragment thereof” from line 1 of claim 10. Similarly, Examiner suggests deleting “or antigen-binding fragment thereof” from lines 1-2 of claims 12, 28, 33, and 34 to avoid potential indefiniteness.
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 § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 8-18, 20, 25, 28-31, and 33 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Lu et al. (WO 2022/042690 A1; Effectively Filed: August 28, 2020; Published: March 3, 2022).
Claims 1 and 25 are indefinite and are interpreted as requiring an anti-CCR8 antibody comprising a HCCDR1, HCCDR2, HCCDR3, LCCDR1, LCCDR2, and LCCDR3 with only one of the aforementioned regions comprising one of the sequences recited in the claim. Lu et al. teaches anti-CCR8 antibodies comprising the six CDRs; see the table on page 68. All anti-CCR8 antibodies listed in the table on page 68 comprise the a LCCDR3 which is 100% identical to instant SEQ ID NO: 6.
Regarding claim 2, Lu et al. teaches an anti-CCR8 antibody comprising a VL of SEQ ID NO: 231 which has 98.1% identity to instant SEQ ID NO: 10. See the alignment below where instant SEQ ID NO: 10 is in the Qy line and Lu et al. SEQ ID NO: 231 is in the Db line.
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266
825
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Regarding claims 8 and 10, Lu et al. teaches that the anti-CCR8 antibodies may be antigen binding fragments or bispecific or multispecific antibody formats; see page 146.
Regarding claim 9, Lu et al. teaches that the antibodies disclosed demonstrated strong binding activity to cynomolgus CCR8-overexpressing CHO cells; see page 220.
Regarding claims 11-14, Lu et al. teaches nucleic acid molecules encoding the anti-CCR8 antibodies, vectors comprising said nucleic acid molecules, and host cells comprising the vectors; see page 146. Further, regarding claims 20 and 33, Lu et al. teaches producing the anti-CCR8 antibodies by culturing a host cell and recovering the antibody; see page 147 and Example 5.
Regarding claims 15 and 28, Lu et al. teaches a pharmaceutical composition comprising the anti-CCR8 antibody and an acceptable carrier; see page 184.
Regarding claims 16-18 and 29-31, Lu et al. teaches administering the pharmaceutical composition comprising the anti-CCR8 antibody to treat CCR8 mediated disease, including solid tumors such as kidney cancer, for example; see pages 240-241.
Thus, Lu et al. anticipates claims 1, 2, 8-18, 20, 25, 28-31, and 33.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 19, 21, 32, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. (WO 2022/042690 A1; Effectively Filed: August 28, 2020; Published: March 3, 2022) as applied to claim(s) 1, 2, 8-18, 20, 25, 28-31, and 33 above.
The teachings of Lu et al. as related to claim(s) 1, 2, 8-18, 20, 25, 28-31, and 33, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Lu et al. teaches that CCR8 is expressed on Tregs, Lu et al. does not teach a method where the subject being treated is limited to a subject who has CCR8 expressing Tregs. Additionally, Lu et al. teaches a pharmaceutical composition comprising an anti-CCR8 antibody and a pharmaceutically acceptbable carrier, but does not teach a method of combining the two.
Regarding claims 19 and 32, Lu et al. teaches that CCR8 is expressed by Tregs and that blocking the interaction of CCL1 and CCR8 reduces the immunosuppressive effect of Tregs and their migration into the tumor microenvironment; see page 133. Lu et al. teaches that targeting CCR8 to clear CCR8+ Tregs in the tumor microenvironment with an anti-CCR8 antibody is a tumor immunotherapy: see page 133.
Regarding claims 21 and 34, Lu et al. teaches a pharmaceutical composition comprising the anti-CCR8 antibody and an acceptable carrier; see page 184.
It would have been obvious to one of ordinary skill in the art to treat a subject comprising CCR8+ Tregs by administering the anti-CCR8 antibody taught by Lu et al. because Lu et al. teaches that the mechanism of anti-tumor action of anti-CCR8 antibodies is blocking the CCL1-CCR8 interaction on Tregs to reduce their intratumor migration and immune suppressive effect. One would have had a reasonable expectation of success and predictability using the anti-CCR8 antibodies to treat a subject comprising CCR8-expressing Tregs because Lu et al. demonstrates that the anti-CCR8 antibody has NK-mediated ADCC activity (see Example 13), that intratumoral Tregs overexpress CCR8 compared to peripheral Tregs (Example 14), and that the anti-CCR8 antibody has anti-tumor activity in vivo (see Example 16).
Further, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to produce the pharmaceutical composition by combining the anti-CCR8 antibody taught by Lu et al. with a pharmaceutically acceptable carrier because Lu et al. teaches a pharmaceutical composition comprising the anti-CCR8 antibody in a pharmaceutically acceptable carrier. It would have been obvious to combine the two components: the anti-CCR8 antibody and the pharmaceutically acceptable carrier to yield the pharmaceutical composition taught by Lu et al. Lu et al. exemplifies administering the anti-CCR8 antibody by intraperitoneal administration (see Example 16). One would have been motivated to combine the anti-CCR8 antibody with a pharmaceutically acceptable carrier, such as a buffer, for example, in order to facilitate intraperitoneal administration.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. (WO 2022/042690 A1; Effectively Filed: August 28, 2020; Published: March 3, 2022) as applied to claim(s) 1, 2, 8-18, 20, 25, 28-31, and 33 above, and in view of McGrath et al. (WO 2021/163064 A2; Published: August 19, 2021).
The teachings of Lu et al. as related to claim(s) 1, 2, 8-18, 20, 25, 28-31, and 33, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Lu et al. teaches CCR8+ Tregs in the tumor microenvironment, Lu et al. does not teach using the anti-CCR8 antibodies for detecting CCR8 expression in a subject sample.
McGrath et al. teaches anti-CCR8 antibodies and using the anti-CCR8 antibodies for diagnosis of diseases or conditions associated with CCR8 expression; see paragraph 0437. McGrath et al. teaches a method comprising contacting a patient sample with the anti-CCR8 antibody and determining the level compared to a reference or control sample; see paragraph 0438. The sample contacted include tissue samples and blood samples; see paragraph 0439. Further, example 2 demonstrates assessing CCR8 expression on Tregs obtained from human tumor biopsies.
It would have been obvious to one of ordinary skill in the art to use the anti-CCR8 antibodies taught by Lu et al. to assess the level of CCR8 in a subject comprising contacting the anti-CCR8 antibody with a sample and determining the level as taught by McGrath et al. Additionally, because McGrath et al. teaches that CCR8 is highest on Tregs obtained from tumor tissue, it would have been obvious to measure CCR8 levels in tumor tissue samples comprising Tregs. Further, since McGrath et al. teaches that CCR8 Tregs suppress effector T cell function in cancer (see paragraph 0022) and that measuring the CCR8 level with an anti-CCR8 antibody can determine if a patient will respond to an anti-CCR8 antibody (see paragraph 0437), one would have been motivated to substitute the anti-CCR8 antibody of McGrath et al. with the anti-CCR8 antibody of Lu et al. as different antibodies have different epitopes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Potentially Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: The anti-CCR8 antibodies or antigen-binding fragments comprising the sets of six CDRs labeled (1) – (10) as recited in claim 1 are free of the prior art.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Holland et al. (WO 2021/142002 A1; Published: July 15, 2021; cited in the IDS filed: May 29, 2024) teaches antibodies or antigen binding fragments that bind human CCR8, polynucleotides encoding said antibodies or fragments, vectors comprising said polynucleotides, pharmaceutical compositions comprising the anti-CCR8 antibodies or fragments, and methods of treating comprising administering the anti-CCR8 antibodies or fragments. However, Holland et al. does not anticipate or render obvious the anti-CCR8 antibodies or fragments thereof comprising the sets of six CDRs recited in claims 1 and 25.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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