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 .
Examiner’s Comment
In the Interview Summary mailed 10/2/2025, in the first line of the section “Other”, the filing date of the new claims should have been 9/5/25 instead of 9/2/25.
It is noted that for claims 33 and 45, which require that the antibody or antigen-binding fragment thereof is administered in sequential combination with the further therapeutically active compound or therapy, “The inventors furthermore conclude that the sequential administration of the therapeutic agents adds additional benefit, if the anti-CCR8 antibody is administered first and if a further therapeutic agent is administered only after an initial reduction of Treg cells (e.g. by at least 50 %) has taken place, e.g. as demonstrated in examples 12.6.5 and 12.6.7.” (p. 271, lines 2-5) This means that for claims 33 and 45, the further therapy will have a beneficial effect only when the sequence of administration begins with the anti-CCR8 antibody followed by the further therapy; however these claims do not require any particular order of or gap between administration of the anti-CCR8 antibody and further therapy. Regardless of administration sequence and of the further therapy, one skilled in the art would still reasonably expect at least the anti-CCR8 antibody or antigen-binding fragment thereof to have a beneficial therapeutic effect. (See also, paragraph bridging pp. 274-275, p. 275, lines 15-17).
Alternative Names
Synonyms for CCR8 are CC-CKR-8, CCR-8, CDw198, CKRL1, CMKBR8, CMKBRL2, GPRCY6, CY6, TER1 as disclosed on p. 45, lines 2-3, of the specification.
Election/Restrictions
Applicant’s election of Group VI in the reply filed on 9/5/2025, and species of therapeutically active compound or therapy that is radiation therapy is acknowledged. The elected species of anti-CCR8 antibody or antigen-binding fragment thereof is acknowledged and is an antibody comprising an HCDR3 of SEQ ID NO:620 (TPP-23411), set of 6 CDRs which are SEQ ID NO:618-620 and 622-624, variable heavy and variable light chain sequence (VH and VL, respectively) of SEQ ID NO:617 and 621, and heavy and light chain sequence (HC and LC) of SEQ ID NO:633 and 634. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Because claim 17 was amended in the response filed 9/5/2025 to be drawn to a method of treating a tumor instead of to a product that is an antibody for use in the treatment of a tumor, the elected group is most similar to Group IX, a method of treating a tumor or disease characterized by the involvement of cells expressing CCR8 by administering an antibody or antigen-binding fragment according to claim 17 as set forth in the restriction mailed 6/18/2025, which requires election of species of anti-CCR8 antibody or antigen-binding fragment thereof (see immediately preceding paragraph for election).
Claims 35-37, 47 and 49-50 are withdrawn from consideration as directed to nonelected species.
Specification
The disclosure is objected to because of the following informalities: On p. 9, lines 13 and 17, “FC” should be --Fc--. On p. 21, line 31 and 35, “Cd” should be --CD--. On p. 49, line 18, it appears “complementary” should be --complementarity--.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
The size of the Sequence Listing created July 30, 2024, recited on p. 1, line 14, is incorrect. Appropriate correction is required. See official data:
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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:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See p. 205 of the specification, line 18: sequences MDYT and YYPD.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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 41 and 54 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 41 and 54 are indefinite because they recite “C is X or S” but there is no C in the sequences. Further, SEQ ID NO:46-48 recite “Xaa can be any naturally occurring amino acid”, which includes C. In the interest of compact prosecution, the claims will be examined as if they instead recited “X is an amino acid different from C.” (See Interview Summary mailed 10/2/2025 for confirmation by Applicant of this intended meaning. Although, it is noted no support in the specification or claims as originally filed could be found for the above alternative definition of X.)
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 41 and 54 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.
Neither the specification nor claims as filed disclose a tyrosine rich domain (TRD) of CCR8 comprising SEQ ID NO:45 wherein Y19 and/or Y28 are sulfated. There is, however, disclosure of SEQ ID NO:45 wherein at least two of Y3, Y14 and Y15 are sulfated.
Claims 17, 24, 31-34, 38-46, 48 and 51-54 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.
There are two overlapping issues of lack of written description for the antibodies used in the claimed method. The overarching one is description of an antibody that can be used therapeutically to treat a tumor and that specifically binds CCR8 and induces ADCC and/or ADCP. A further issue is for antibodies used in the methods that require even more specific functional properties (claims 32, 34, 39, 40, 41, 44, 46 and 52-54).
The specification extensively discusses the difficulty of making antibodies that specifically bind CCR8, especially those that have the therapeutic ability to treat a tumor in a subject. Example 3 reviews prior art antibodies, where it is stated (p. 205, lines 24-25), “Prior art antibodies for chemokine receptors and in particular for CCR8 often suffer from low specificity….” “In summary, antibodies specifically recognizing human CC chemokine receptors are rare for some members of this target class. The low rates are in line with results for further commercially available antibodies sold for human chemokine receptors.” (p. 206, lines 18-20) Because the methods of producing prior art anti-CCR8 antibodies is different than that of the instant application, it is concluded (p. 5, lines 6-10), “In consequence, the antibodies according to the current invention are assumed to deviate in structure and function from the aforementioned prior art antibodies, e.g. at least in their affinity for sulfated CCR8, in their affinity for unsulfated CCR8, in their way and degree of modulating receptor signaling, in their internalization behavior, in cross reactivity, in clearance and pharmacokinetic behavior and finally in Treg depletion and/or efficacy for therapeutic applications.” This suggests the antibodies with the properties used in the instant methods are not common or especially easy to make. One skilled in the art could not have readily envision the structures of a representative number of species of the genus of CCR8-binding antibodies that meet functional requirements of the antibodies used in the claims.
It is stated in AbbVie Deustschland GmbH v. Janssen Biotechnology, Ltd., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., Inc., 323 F.3d at 964, “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date…” Applicant has not disclosed a structure-function correlation for the genus of antibodies having the required functions. Even noting that the human anti-human CCR8 antibodies had more tyrosine amino acids in the HCDR3 compared to a random human HCDR3 (Example 9), this does not provide sufficient structural specificity to describe the genus. It is discussed on p. 8, lines 19-22, “While, in theory, the diversity of HCDR3 regions is almost unlimited, in practice the generation of the antibody repertoire diversity appears to be carefully regulated by multiple mechanisms, which yield an in vivo repertoire that is restricted in its diversity and constrained in its range of antigen-binding sites.”
In Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) the court discussed whether an antibody is adequately described by describing a newly characterized antigen. Specifically, the court referred to the decision in Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011). In that case, the patentee claimed a genus of antibodies containing a human variable region that has particularly desirable therapeutic properties: high affinity, neutralizing activity, and A2 specificity. Despite the fact that the specification disclosed human TNF-α protein, the court ruled that that the generic antibody claims at issue were invalid for lack of written description, despite the disclosure of the structures of more than one species of antibody encompassed by the genus. The fact pattern is similar to the instant case. Specifically, in the instant case the sulfated CCR8 TRD is identified, while the specific structures for the anti-CCR8 antibodies are not. As in the court case, the instant claims recite a genus of anti-CCR8 antibodies that have a desirable property, i.e.,specific binding of CCR8, ability to induce ADCC and/or ADCP and that can be used to treat a tumor. Following the finding in Centocor, the instant claims are found to lack adequate written description. The court in Amgen v. Sanofi citing Centocor again provides an analogy for the antibody-antigen relationship as not quite a lock and key relationship but rather providing a lock and then searching for a key on a ring with a million keys on it. The court concludes that the “newly characterized antigen” test flouts basic legal principles of the written description requirement, reasoning that section 112 requires a written description of the invention, whereas the newly characterized antigen test allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen. Accordingly, since the instant fact pattern fits the “newly characterized antigen” scenario, wherein the specification describes the structure of the target/antigen but not the structure of the genus of anti-CCR8 antibodies but only limited species thereof, the claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre- AIA ), first paragraph. Given the large structural variability permitted by the claims for the structure of each antibody and limited disclosure of the specification, the specification fails to associate structure with the required binding and therapeutic function commensurate in scope with the genus of antibodies in the claims. The description of a newly characterized antigen, similar to description of the specific sulfated TRD of human, cynomolgus and mouse CCR8, should not be considered adequate written description of a claimed antibody to that characterized antigen, even when preparation of such an antibody is routine and conventional (Id.). Although, according to the instant specification, antibody generation and identification using sulfated CCR8 TRD targets is neither routine nor conventional.
Claims 32, 34, 39, 40, 41, 44, 46 and 52-54 require anti-CCR8 antibodies with additional particular functional properties. It is not enough that the antibodies merely bind CCR8, according to the claims they must bind a CCR8 that has a sulfated tyrosine rich domain (TRD) and/or has the ability to deplete intratumor regulatory T cells (Tregs) by at least 50% and/or increase intratumoral CD8 cell ratio to Tregs by at least a factor of 2. Some claims have particular mammalian CCR8 cross reactivity requirements. There is no structural limitation for the antibodies in the claims. The genus of antibodies encompassed by the claimed methods do not meet the written description provision of 35 USC 112(a).
Claims 32 and 44 require the further therapeutically active compound or therapy is administered after treatment with the antibody or antigen-binding fragment thereof results in intratumor Treg depletion of at least 50%. Claims 34 and 46 require that the dose of the further therapeutically active compound or therapy is administered after administration of the antibody or antigen-binding fragment thereof has (a) effected an increase of the intratumor CD8 cell to Treg cell ratio at least by a factor of 2 or (b) resulted in intratumor Treg depletion of at least 50%. Claims 39 and 52 limit the antibody or antigen-binding fragment thereof to one that binds human CCR8 and also binds CCR8 from one or both of mouse and cynomolgus. The elected antibody is TPP-23411 and is identical to TPP-21360, except that TPP-23411 lacks a C-terminal lysine (p. 229). There is no data for either antibody related to percent Treg depletion or CD8 cell to Treg cell ratio.
In terms of claims 32, 34, 44 and 46, what the specification discloses is data primarily for antibody TPP15285, a surrogate anti-mouse CCR8 antibody that stands in for an anti-human CCR8 antibody (e.g., p. 239, lines 4-5 and 13). TPP15285 comprises a mouse IgG2a Lambda Fc domain (Table on p. 26). Even with this anti-mouse antibody, the results do not fully support the functional requirements of the claims. That is, the antibody’s ability to deplete intratumoral Tregs by at least 50% and/or increase intratumor CD8:Treg ratio by at least a factor of 2 without any other therapeutic agent, that is, prior to administration with a further therapeutically active compound or therapy. Table 12.6.3.1 shows EMT-6 intratumoral cell populations from tumor bearing mice, with the antibody treatment (1 mg/kg) leading to a greater than 50% depletion of Tregs and increase in CD8:Treg cells of greater than 2 fold. However, at a higher antibody dose the effects were different. Table 12.6.6.1 shows EMT-6 intratumoral cell populations from tumor bearing mice, with the antibody treatment (5 mg/kg) leading to an increase in absolute Treg cell number but also an increase in CD8 cells such that the CD8+ cell/T reg ratio is at least 2 times greater than without antibody treatment, even though there is no intratumoral Treg depletion (See also Table 12.4.1.2). The same trend can be seen in the experiment represented in Table 12.6.7.1, which shows Lewis lung carcinoma intratumoral cell populations from the carcinoma bearing mice (antibody dose of 10 mg/kg). Table 12.6.5.1 shows results from MB49 intratumoral cell populations in tumor bearing mice, with a reduction in CD8:Treg ratio (antibody dose of 10 mg/kg). Table 12.6.4.1 shows intratumoral cell populations in C38 tumors, with the CD8:Treg ratio increased by more than a factor of 2 but the percentage of Tregs depleted only by about 10% (antibody dose of 5 mg/kg). While the data are different when the second therapeutic agent was added, the claims require the limitation directed to Treg depletion and CD8 cell to Treg cell ratio be attained prior to the addition of the further therapeutically active compound or therapy. Clearly from Example 12, in many cases the combination of anti-CCR8 antibody treatment must be combined with a following treatment of further therapeutically active compound or therapy in order to achieve the recited Treg depletion level and CD8:Treg cell ratio. Additionally, only a single CCR8 antibody was used. Further, Table 12.5.1 shows that antibody dosage matters in attaining the required results as does number of treatments, with Table 12.5.1 showing results at 24 hours after the second treatment (see also, e.g., Tables 12.4.1 and 12.4.2.3). One skilled in the art could not readily envision the structure of a representatively number of species of the genus of CCR8-binding antibodies that meet these functional requirements for the antibodies used in the claims.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [they] invented what is claimed.” (See Vas-Cath at page 1116).
For claims 32, 34, 44 and 46, it does not appear the specification discloses a genus of antibodies specifically binding CCR8, let alone a representative number of species thereof, that have the property of depleting Tregs intratumorally by at least 50% and/or increasing intratumor CD8 cell to Treg Cell ratio by at least a factor of 2 in the absence of other further therapeutically active compound or therapy.
In terms of claims 39 and 52, Table 10.1.1.6 lists isolated antibodies that bound both human and cynomolgus CCR8. These antibodies meet the written description for claims 39 and 52. It appears that antibodies binding murine CCR8 TRD were isolated (e.g., Table 10.1.1.5 and Example 8), but they do not necessarily bind human or cynomolgus CCR8 (Table 10.1.2.1). The specification discusses (Example 2) that human and cynomolgus CCR8 protein share 94.37% identity, with the TRD thereof sharing 68% identity, but only 71% identity is shared between mouse and human CCR8 and 52% over the TRD. This supports the lack of reasonable expectation that an anti-CCR8 antibody binding human or cynomolgus CCR8, particularly the TRD, would also bind murine CCR8, including in the TRD. As stated on p. 9, lines 1-3, “According to the current invention, cross reactive antibodies for CCR8 can be generated in particular by using small sulfated tyrosine comprising motifs which have a higher conservation between species,…” This again, points to the difficulty of making anti-CCR8 antibodies that are cross reactive between animal species other than those with significant sequence identity, e.g., human and cynomolgus monkey.
Further, with the exception of the particular anti-CCR8 antibodies shown in the specification that bind both human and cynomolgus CCR8 for claims 39 and 52, and more generally for claims 40, 41, 53 and 54, wherein the antibody or antigen-binding fragment thereof is prepared such that it specifically binds the sulfated TRD of CCR8 and is one of the antibodies disclosed in the specification (e.g., Table 7.2.a and 7.2.b), the skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Claims 40 and 53 and dependent claims 41 and 54 require that the method comprises preparing the antibody or antigen-binding fragment thereof using a sulfated polypeptide or conjugate thereof comprising a tyrosine rich domain (TRD) of CCR8; however, there is no disclosure of an antibody with the properties required by the claims, i.e., specifically binds CCR8 and induces at least one of ADCC and ADCP (or both for claim 42), wherein the antibody does not bind the TRD of CCR8. As the claims are written there is no limitation for the polypeptide or conjugate comprising the TRD, nor that the antibody prepared using the polypeptide or conjugate binds some part of the TRD. The antibody is being claimed by what it does instead of what it is. The specification teaches that anti-CCR8 antibodies were identified by screening a phage display library using a cynomolgus or human CCR8 N-terminal domain sulfated at Y3, Y15 and Y17 and with N-terminal biotinylation (Table 6.1 and Example 6, apparently SEQ ID NO:43-46). However, the claims require only that the antibody be prepared using a sulfated polypeptide or conjugate thereof comprising a CCR8 TRD. If the polypeptide or conjugate is large or structurally arranged such that the TRD is not particularly accessible, the genus of resulting antibodies would not reasonably be expected to bind the CCR8 sulfated TRD and, therefore, would not meet the other functional limitations required by the claims from which these claims depend.
Antibodies TPP-23411 and -21360 had little or no binding to unsulfated CCR8 TRDs (Table 10.1.2.1), showing sulfation of the protein, i.e., of the TRD of CCR8, is important for antibody binding. (See also Table 10.1.3.1 p. 232.) This is also shown in Table 10.1.2.3, in which three anti-CCR8 antibodies of the invention were shown to have no binding to human or cynomolgus TRD or N-terminal portions in the absence of sulfation. Therefore, it reasonably appears that the antibodies contact some portion of the sulfated TRD to allow binding. Again, in reference to Amgen v. Sanofi (Id.), a method of treatment using an antibody claimed only by function, e.g.¸ specifically binding CCR8 and having ADCC and/or ADCP activity, or by a general method of preparation is not sufficient to describe the antibody itself or allow the skilled artisan to readily envision the antibody necessary for the claimed method of treatment. While the specification discloses some antibodies that would reasonably be expected to function in the claimed method (Tables 7.2.a and 7.2.b), the genus of antibodies extends well beyond those disclosed without sufficient support for the genus.
Claims 17, 24 and 31-54 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 a method of treating a tumor in a subject in need thereof comprising administering an effective amount of an antagonistic anti-CCR8 antibody or antigen-binding fragment thereof wherein the antibody binds the tyrosine rich domain (TRD) of CCR8, wherein the TRD comprises SEQ ID NO: 43, wherein at least two of Y3, Y15, and Y17 are sulfated; SEQ ID NO: 46, wherein at least two of Y3, Y15, and Y17 are sulfated; SEQ ID NO: 44, wherein at least two of Y3, Y15, and Y17 are sulfated; SEQ ID NO: 47, wherein at least two of Y3, Y15, and Y17 are sulfated SEQ ID NO: 45, wherein at least one of Y3, Y14, Y15, Y19, and Y28 are sulfated; and SEQ ID NO: 48, wherein at least two of Y3, Y14, and Y15 are sulfated, does not reasonably provide enablement for wherein the antibody does not bind the TRD of CCR8 comprising sulfated tyrosine residues and is not antagonistic. 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.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claims are drawn to a method of treating a tumor comprising administering an antibody or antigen-binding fragment thereof that specifically binds CCR8 and induces at ADCC and/or ADCP (or both for claim 42 and dependent claims thereof). However, there is no CCR8 antibody structure recited in the claims. Additionally for claims 40, 41, 53 and 54, none of the claims recite a structure for an antibody that binds a first sulfated polypeptide which comprises the TRD of CCR8. Also, to function in the claimed invention, it appears the antibodies must be antagonists. Most of the antibodies tested were “fully efficacious antagonists” of G-protein-dependent calcium signaling, blocking CCR8 binding to its ligand CCL1, which is responsible for inducing G-protein dependent calcium signaling (p. 119, lines 5-7, Ex. 10.4.3). The specification describes how difficult it has been to obtain anti-CCR8 antibodies that can function in an antitumor capacity. It notes (p. 2, lines 25-32) that on average less than 30% of a chemokine receptor is extracellular and “antibodies generated against peptides corresponding to extracellular domains of chemokine receptors often fail to recognize the intact receptor on the cell, possibly due to differences in secondary structure. In consequence, researchers in this field have had a low success rate in developing antibodies…” Even though the specification says that generation of anti-murine CCR8 antibodies “is slightly less difficult,” the prior art discusses that “the production of anti-mouse cytokine receptor monoclonal antibodies is a demanding challenge and that antibodies against murine chemokine receptors is comparably scarce, despite the time that has passed since their amino acid sequences were first reported.” (paragraph bridging pp. 2-3) Antibodies made using whole cells expressing the chemokine receptor “are often characterized by off-target binding and low specificity for the chemokine receptor.” (p. 4, lines 3-10). The antibodies disclosed in the specification were all made to sulfated CCR8 N-terminal domain TRD-comprising peptides (see Table 4.1). As stated in the specification (p. 5, lines 1-10), “Use of an isolated sulfated polypeptide comprising the TRD of a chemokine receptor or transmembrane protein as antigen influences both, structural and functional features of the set of obtained antibodies, as discussed elsewhere herein.⁋ In consequence, the antibodies according to the current invention are assumed to deviate in structure and function from the aforementioned prior art antibodies, e.g. at least in their affinity for sulfated CCR8, in their affinity for unsulfated CCR8, in their way and degree of modulating receptor signaling, in their internalization behavior, in cross reactivity, in clearance and pharmacokinetic behavior and finally in Treg depletion and/or efficacy for therapeutic applications.” Seven prior art anti-CCR8 antibodies were evaluated and found to have no or low specificity for human CCR8 (p. p. 206, lines 2-8 and Table 3.1). “In summary, antibodies specifically recognizing human CC chemokine receptors are rare for some members of this target class.” (p. 206, lines 18-19) It is noted that only claims 38, 39, 51 and 52 require binding to human CCR8.
The antibodies are, however, required to specifically bind CCR8 (i.e., wherein the antibody specifically recognizes the antigen and does not substantially recognize or bind to other molecules and the binding is dependent on a particular structure of the antigen, see p. 47, lines 6-16) and induce ADCC and/or ADCP and be used to treat cancer. As admitted in the specification, the prior art discloses few antibodies that would likely meet these requirements (supra). It discloses few or none that meet the limitations of the dependent claims. The specification states (p. 2, lines 28-30), “Furthermore, antibodies generated against peptides corresponding to extracellular domains of chemokine receptors often fail to recognize the intact receptor on the cell... In consequence, researchers in this field have had a low success rate in developing antibodies....” As discussed in the specification on p. 114, lines 2-21, it was surprising that the CDRH3s of the CCR8 antibodies of the instant application have a higher than expected tyrosine and histidine content. It is suggested that this is caused by the particular sulfated motif of the CCR8 antigen, with a high tyrosine/histidine content in the HCDR3 promoting specific recognition of the antigen. It is believed “this specific recognition influences the characteristics of the obtained antibodies as a modulator of CCR8,...” Further on p. 206, lines 19-21, it is acknowledged, “In summary, antibodies specifically recognizing human CC chemokine receptors are rare for some members of this target class. The low rates are in line with results for further commercially available antibodies sold for human chemokine receptors.” This suggests the antibodies with the properties used in the instant methods are not common or especially easy to make.
Even if the antibody or antigen-binding fragment binds CCR8, that is not sufficient for treatment of cancer or another disease. It is reported in the specification that antibody TPP-23411 did not significantly induce phosphorylation of AKT (Fig. 30 and Ex. 10.4.2, p. 118, lines 27-29). Further (p. 119, lines 1-3), “Antibodies or fragments which show no induction of G-protein independent signaling pathways such as AKT or ERK 1/2 phosphorylation are assumed to have advantages in therapy because induction of G-protein dependent signaling may lead to unwanted effects and side effects.” Most antibodies tested were fully antagonists of G-protein-dependent calcium signaling, blocking CCR8 binding to its ligand CCL1, which is responsible for inducing G-protein dependent calcium signaling (p. 119, lines 5-7, Ex. 10.4.3). As explained in the specification on p. 171, lines 4-13, regulatory T cells (Tregs) suppress effector T cell function and, thereby, promote tumor growth. This includes suppression of tumor responsive T cells in the tumor microenvironment. Because G-protein-coupled receptor family member CCR8 is predominantly expressed on the surface of activated immune suppressive Tregs frequently found in tumors, these Tregs can be targeted without impacting resting Tregs or other immune cells, which do not significantly express CCR8. “Thus, targeting CCR8 may be superior in terms of both efficacy and safety. This mode of action can thus be used in tumors with intra-tumoral Treg,…”
Therefore, for the reasons discussed above, including the breadth of the claims in terms of an antibody or antigen-binding fragment thereof that specifically binds CCR8 and induces ADCC and/or ADCP, i.e., the lack of any structural limitation for the antibody, the support by the prior art of the complexity and difficulty of generating antibodies the bind chemokine receptors, especially human CCR8, and the limited working examples of anti-CCR8 antibodies that can function within the context of the claimed method of treatment of a tumor, it would require undue experimentation to make and use the claimed invention.
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.
Claim Rejections - 35 USC § 102
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.
Claim(s) 17, 24, 31-34, 38, 40, 42-45, 48, 51 and 53 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2021/0277129 A1 (McGrath, cited in the IDS filed 5/16/20204) in light of CN 118852430 A (Google English translation also attached).
US 20210277129 Al (McGrath) does not receive benefit of priority 2/14/2020 for sulfated CCR8 epitope but does for treatment including a chemotherapeutic such as oxaliplatin or doxorubicin and possession of ADCC activity by human IgG1 chimeric antibodies 1-K17 and 7-B16 (Fig. 6). It teaches that CCR8 is preferentially expressed on tumor-infiltrating (TIL) regulatory T cells (Treg), which are immune suppressing cells found in the tumor microenvironment ([0049] and Figs. 3A-3B). It teaches treatment of solid cancers with tumor infiltrating Tregs that express CCR8 by administering to a subject with cancer an effective amount of antibody 1-K17 or 7-B16 ([0299]). Treatment can also be of a blood cancer, e.g., B- or T-cell lymphoma ([0303]). The antibody may be administered in conjunction with another mode of anti-cancer treatment, including radiation therapy or chemotherapy ([0316]). Administration may be sequential, including wherein the antibody is administered sequentially with a second therapeutic agent ([0317]). The second agent may be gemcitabine, docetaxel, doxorubicin, cisplatin, paclitaxel or oxaliplatin ([0322]). An anti-mouse CCR8 monoclonal antibody that was Fc-competent caused depletion of TIL Tregs and reduced tumor growth in an in vivo MC38 syngeneic mouse model ([0054]-[0055]). Figs. 8A-8B show that in that system intratumoral Treg depletion was at least 50%.
Even though the earliest priority application (US 62/976,869) of McGrath teaches anti-CCR8 antibody 7-B16 but is silent with respect to how antibody 7-B16 was prepared, McGrath teaches antibodies that bind CCR8 (Example 3-13), including 7-B16 that binds a sulfated epitope [703]. The epitope comprises 4 tyrosine residues, all of which could be sulfated (Y3, Y15, Y16, Y17). This epitope (amino acids 406-440 of SEQ ID NO:128) comprises instant SEQ ID NO:43 (amino acids 1-24 of the epitope). It reasonably appears absent evidence to the contrary that antibody 7-B16 was prepared using a sulfated polypeptide comprising a tyrosine rich domain (TRD) of CCR8.
CN 118852430 teaches (Fig. 7 and Table 5) anti-CCR8 antibodies and that ADCP activity on human CCR8 target cells of several anti-CCR8 antibody clones was compared to antibody 7-B16.001. The the ADCP activity of clone 2122-241HL is comparable to that of 7-B16.001 (a variant of 7-B16). Therefore, it reasonably appears that antibody 7-B16 has measurable ADCP activity. Note that Table of Certain Sequences (p. 79 of the specification) of McGrath shows that antibodies 7-B16 and 7-B16.001 have the same heavy and light chain CDR1-3 regions.
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.
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.
Claim(s) 17, 24, 31, 33 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/181425 A1 (WO’425, cited in the IDS filed 5/16/2024) in view of Liu et al. (J. Haematol. Oncol. 11:104, 15 pages, 2018).
WO’425 teaches anti-mouse CCR8 antibody SA 214G2, which has the ability to induce antibody-dependent cell mediated cytotoxicity (ADCC, Figs. 8-9). Figs. 20-21 shows that a xenograft mouse model with colon cancer cell lines CT26 treated with the antibody resulted in reduced tumor volume. WO’425 does not teach addition of radiation as a further therapeutic therapy.
Liu et al. teaches radiotherapy (RT) for malignant tumors has been used for decades and in about 50% of all cancer patients, both those newly diagnosed and with persistent or recurrent tumors (p. 1/15, col. 1). It is reported, “[O]ther studies have found that this immune-mediated anti-tumor effect of RT could also trigger the regression of metastatic tumors that were distant from the irradiated field, which is the so-called abscopal effect.” There are many clinical trials combining radiation therapy with CTLA-4/PD-1/PD-L1 inhibitors s shown in Table 3. Research continues into whether administration should be concurrent or sequential (p. 10/15, col. 1, second paragraph). It is concluded (p. 11/15, col. 2, paragraph 2), “With the development of cancer immunotherapy, especially immune checkpoint inhibitors, the abscopal effect of RT has become more meaningful, since the in situ vaccination that is generated by RT can be substantially potentiated by immunotherapy. Exploiting the synergistic anti-tumor effect of these two treatments is encouraging because of its effective potential to improve the OS and PFS of patients with malignant tumors.”
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to have treated a tumor in a subject in need using the method of WO’425 with the addition of radiation therapy to further the treatment in view of the teachings of Liu et al. related to the advantages of treatment with radiotherapy combined with immunotherapy. Due to long term and common use of radiation therapy in cancer treatment and success with certain immunotherapy, one skilled in the art would have been motivated to use the combination and would have had a reasonable expectation of beneficial effects with the combination.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 17, 24, 31, 33, 38, 39, 42, 43, 45, 48, 51 and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-16 of U.S. Patent No. 12,065,497 in view of US 2021/0277129 A1 (McGrath).
Both the instant claims 17 and 42 and patented claim 1 are drawn to a method of treating a tumor in a subject by administering an antibody or antigen-binding-fragment thereof that specifically binds CCR8 and in the case of the patented claim wherein the antibody is claimed by heavy and light chain CDR sequences. Instant claims 17 and 42 do not claim the antibody by any particular structure but do require the antibody to induce ADCC and/or ADCP, and require a further therapeutically active compound or therapy. The species of antibodies used in the method of the patent anticipate the genus of the instant claims. The properties of ADCC and ADCP being inherent to the structure of the antibodies. The patent does not claim administration of the antibody or antigen-binding fragment thereof with a second therapeutic compound or therapy which is not a target of a checkpoint protein.
Additionally, McGrath teaches treatment of a tumor with tumor infiltrating Tregs that express CCR8 by administering to a subject with the tumor an effective amount of anti-CCR8 antibody 1-K17 or 7-B16 ([0299]). The anti-CCR8 antibodies possess ADCC activity by human IgG1 chimeric anti-CCR8 antibodies 1-K17 and 7-B16 (Fig. 6). Antibodies having a mIgG2a Fc domain led to tumor infiltrating Treg depletion and reduced tumor growth in an in vivo MC38 syngeneic mouse model ([0054]-[0055] and Example 11). The antibody may be administered in conjunction with another anti-cancer treatment, including radiation therapy or chemotherapy ([0316]) e.g., gemcitabine, docetaxel, doxorubicin, cisplatin, paclitaxel or oxaliplatin ([0322]). Administration may be sequential, including wherein the antibody is administered sequentially with a second therapeutic agent ([0317]).
It would have been obvious wherein treatment of a tumor with an anti-CCR8 antibody as set forth in the patent claims additionally comprised administration with a further therapeutic agent or therapy that was chemotherapeutic agent or radiation as taught by McGrath and which second therapies were well known and routinely used for the treatment of tumors.
Claims 17, 24, 31, 33, 38, 39, 42, 43, 45, 48, 51 and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 18, 13 and 25 of copending Application No. 19/110,032 (‘032) in view of US 2021/0277129 A1 (McGrath) in light of Campbell et al. (Canc. Res. 81(11):2983-2994, 01 June 2021).
Both the instant claims 17 and 42 and claim 1 and 2 of ’032 are drawn to a method of treating a subject by administering an antibody or antigen-binding-fragment thereof that binds CCR8. The instant method is for treatment of a tumor and with an anti-CCR8 antibody that induces ADCC and/or ADCP. The antibody of ‘032 having the CDRs of SEQ ID NO: 2-4 and 6-8 and heavy and light chain of SEQ ID NO:17 and 18, respectively (claim 17), is TPP23411 as defined in the table on p. 12 of the specification and which inherently induces ADCC and ADCP (Examples 5 and 6 of ‘032) and binds human and cynomolgus CCR8 (p. 70, middle). The specification of ‘032 sets forth the following definition (middle of p. 2):”TPP-23411 is a fully human IgG antibody and was generated with a phage display approach using chemically synthesized peptides comprising the sulfated N-term of human or cynomolgus CCR8 as epitopes.” The claims of ‘032 do not recite administration of a further therapeutic agent or therapy that does not target a checkpoint protein.
McGrath teaches treatment of a tumor with tumor infiltrating Tregs that express CCR8 by administering to a subject with the tumor an effective amount of anti-CCR8 antibody 1-K17 or 7-B16 ([0299]). The anti-CCR8 antibodies possess ADCC activity by human IgG1 chimeric anti-CCR8 antibodies 1-K17 and 7-B16 (Fig. 6). Antibodies having a mIgG2a Fc domain led to tumor infiltrating Treg depletion and reduced tumor growth in an in vivo MC38 syngeneic mouse model ([0054]-[0055] and Example 11). The antibody may be administered in conjunction with another anti-cancer treatment, including radiation therapy or chemotherapy ([0316]) e.g., gemcitabine, docetaxel, doxorubicin, cisplatin, paclitaxel or oxaliplatin ([0322]). Administration may be sequential, including wherein the antibody is administered sequentially with a second therapeutic agent ([0317]). The antibody is administered once every week or every three weeks in the range of 10 ug/kg to 100 mg/kg body weight per dose ([0310]-[0311]). The antibody may be administered intravenously ([0315]).
It would have been obvious wherein treatment was of a tumor with an anti-CCR8 antibody as set forth in the copending claims additionally comprised administration with a further therapeutic agent or therapy that was a chemotherapeutic agent or radiation as taught by McGrath and which second therapies were well known and routinely used for the treatment of tumors.
This is a provisional nonstatutory double patenting rejection.
Claims 17, 24, 31, 33, 38, 40, 42, 43, 45, 48, 51 and 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 18, 31, 32 and 38-40 of copending Application No. 18/666,545 (‘545) in view of US 2021/0277129 A1 (McGrath) in light of Campbell et al. (Canc. Res. 81(11):2983-2994, 01 June 2021).
Both the instant claims 17 and 42 and claim 16, 18 and 31 of ’545 are drawn to a method of treating a subject having a tumor by administering an antibody or antigen-binding-fragment thereof that binds CCR8. Both recite wherein the anti-CCR8 antibody binds a sulfated CCR8 (see claim 12 of ‘545, which the method claims depend from, and claims 40 and 51 of the instant application) The instant claims recite the anti-CCR8 antibody induces ADCC and/or ADCP, which is not a limitation in ‘545. ‘545 does not claim administration of a further therapeutic agent or therapy which does not target a checkpoint protein as required by the instant claims.
McGrath teaches treatment of a tumor with tumor infiltrating Tregs that express CCR8 by administering to a subject with the tumor an effective amount of anti-CCR8 antibody 1-K17 or 7-B16 ([0299]). The anti-CCR8 antibodies possess ADCC activity by human IgG1 chimeric anti-CCR8 antibodies 1-K17 and 7-B16 (Fig. 6). Antibodies having a mIgG2a Fc domain led to tumor infiltrating Treg depletion and reduced tumor growth in an in vivo MC38 syngeneic mouse model ([0054]-[0055] and Example 11). The antibody may be administered in conjunction with another anti-cancer treatment, including radiation therapy or chemotherapy ([0316]) e.g., gemcitabine, docetaxel, doxorubicin, cisplatin, paclitaxel or oxaliplatin ([0322]). Administration may be sequential, including wherein the antibody is administered sequentially with a second therapeutic agent ([0317]). The antibody is administered once every week or every three weeks in the range of 10 ug/kg to 100 mg/kg body weight per dose ([0310]-[0311]). The antibody may be administered intravenously ([0315]).
Campbell et al. teaches that (p. 2988, col. 1, second paragraph), “The mouse IgG2a isotype strongly engages Fc receptors to promote antibody-dependent cellular cytotoxicity (ADCC) and antibody-mediated cellular phagocytosis (ADCP),…” Therefore, it is more likely than not that an anti-CCR8 antibody, which is an IgG2a antibody, such as was shown by McGrath to reduce tumor infiltrating Tregs to induce ADCC and ADCP. Campbell et al. is not necessary for obviousness, but only provided to show the inherent properties of mIgG2a-containing antibodies.
It would have been obvious wherein treatment was of a tumor with an anti-CCR8 antibody as set forth in the patent claims additionally comprised administration with a further therapeutic agent or therapy that was chemotherapeutic agent or radiation as taught by McGrath, which second therapies were well known and routinely used for the treatment of tumors.
This is a provisional nonstatutory double patenting rejection.
Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Mutalithas et al. (Clin. Exper. Allergy, 40:1175-1185, 2010) teaches mouse antibody 433H specific for human CCR8 (p. 1177, col. 1, first paragraph). It was obtained by injecting mice three times intraperitoneally with transfected COS cells that overexpressed CCR8. Hybridoma antibody supernatants were screened by FACS for selection of clones binding the transfectants with nontransfected COS cells as the negative control. Clones were also tested for their ability to block cell chemotaxis toward CCR8 ligand CCL1. “Purified 433H mAb was shown to be specific for CCR8 by FACS and chemotaxis inhibition assays using a panel of cell lines transfected with a comprehensive panel of chemokine receptors (data not shown).” Mutalithas et al. is cumulative with McGrath for teaching an anti-CCR8 antibody that possess ADCC and ADCP activity (see below).
BD Biosciences teaches monoclonal mouse anti-human CCR8 antibody clone 433H, which is an IgG2a isotype. In light of Campbell et al., (Canc. Res. 81(11):2983-2994, 01 June 2021, supra, p. 2988, col. 1, second paragraph) teaching that “The mouse IgG2a isotype strongly engages Fc receptors to promote antibody-dependent cellular cytotoxicity (ADCC) and antibody-mediated cellular phagocytosis (ADCP),” it is more likely than not that antibody 433H, which is an IgG2a antibody as disclosed by BD Bioscience, induces ADCC and ADCP.
US 20090220486 A1 (cited in the IDS filed 05/16/2024) teaches consensus antibodies that bind sulfated tyrosine epitopes, including of CCR8 [0136]. The antibody sequence is very generic, and no particular CCR8 sulfation sites are disclosed. Further, the antibodies are not considered to specifically bind CCR8 as defined in the instant specification (p. 47, lines 14-18).
US 20080274100 A1 (cited in the IDS filed 05/16/2024, shares inventors with US 20090220486) teaches consensus antibodies that bind sulfated epitopes of CCR8 (claims 1-4). As with the immediately preceding US pregrant publication, the consensus antibodies of the reference cannot be considered to specifically bind CCR8.
Luderman et al. (Brit. J. Pharmacol. 171:1167-97, 2014, cited in the IDS filed 5/16/20204) discusses tyrosine sulfation of chemokine receptors, including CCR8 (see, e.g., Table 1) and its role in chemokine recognition. This reference is provided to show the state of the art several years prior to the effective filing date of the invention.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
December 6, 2025