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 .
Election/Restrictions
Applicant’s election of Group VII and species of biomarker which is PD-L1 in the reply filed on 09/05/2025 is acknowledged. 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)).
Claims 12 and 13 are drawn to nonelected inventions and claims 33-37 and 42-44 are drawn to nonelected species. As a result, they are not currently under examination. Group VII is restricted to wherein the seven transmembrane receptor is CCR8.
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.
Claim Interpretation
In claim 27, the isolated anti-CCR8 antibody or antigen-binding fragment thereof is administered “in combination with an antibody or small molecule targeting and/or inhibiting PD1 or PD-L1.” This is being interpreted as meaning that the antibody and small molecule both target and/or inhibit PD-1 or PD-L1, instead of that the antibody is a generic antibody, without any limitation about to what it binds and/or activity it has, while it is only the small molecule that targets and/or PD-1 or PD-L1.
In claims 39, 40 and 41, the phrase “antibody, an antigen-binding fragment, or a conjugate thereof” is being interpreted as meaning the antibody, an antigen-binding fragment thereof or a conjugate thereof, i.e., the antigen-binding fragment and conjugate are of the antibody. However, this should be made clear in the claims.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
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.
Specification
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: METHOD OF TREATING WITH CCR8 ANTIBODIES
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.
Claim Objections
Claim 27 and 31 are objected to because of the following informalities: In claim 17, line 4, “PD1” should be --PD-1-- for consistency. In claim 31, line 1, “sensitive for treatment” should be --sensitive to treatment--. Appropriate correction is required.
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.
Claim 45 is 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 claim 18, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 45 is indefinite because it is incomplete for omitting the relationship between the determination of therapeutic success and the comparison of biomarker level in the tumor compared to in a reference sample or value. The claim does not recite how the biomarker level comparison relates to therapeutic success (or lack thereof). See MPEP § 2172.01.
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.
Claim 27 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 27 is drawn to a method of treatment comprising administering in addition to the isolated anti-CCR8 antibody or antigen-binding fragment thereof an antibody or small molecule targeting and/or inhibiting a checkpoint protein. While antibodies that bind and/or inhibit checkpoint proteins were well known before the effective filing date of the invention, this is not the case for small molecules that bind and/or inhibit checkpoint proteins. The specification discloses no small molecules meeting the limitations of the claims. In a journal article by Lin et al. (Eur. J. Med. Chem. 186:111876, ePub Nov. 2019) entitled “Progress in PD-1/PD-L1 pathway inhibitors: From biomacromolecules to small molecules”, a number of small molecule checkpoint inhibitors are discussed, but only in terms of providing “rationale for further optimization of small-molecule compounds.”, being “significant for further compounds development.”; “could be employed as a promising lead for further discover of small-molecule PD-1/PD-L1 inhibitors.”; “up to now these anti-PD-1 compounds are still in the clinical proof of concept stage.”; making “them useful starting point for the design of the potential small-molecule inhibitors.” (p. 16, last full sentence; p. 20, col. 1, end of second paragraph, and col. 2, end of first paragraph; p. 21, end of col. 1; p. 23, col. 1, end of first paragraph, respectively). That is, they are not described as ready to be used therapeutically. The actions of two small-molecules under development are also discussed, but their structures had not been disclosed (section 2.3.5, beginning p. 24, col. 1, second paragraph). Lin et al. concludes (p. 25, col. 1, last paragraph), “Much progress has been achieved over the past decades, as represented by several clinically approved mAbs [139]…. However, the flat, large and extremely hydrophobic interface induced by mAbs in PD-1 and PD-L1 poses significant challenges for small-molecule design [140]. The slowly emerging structural information about binding molecules also puts obstacles in the progress of small-molecule inhibitors. ⁋ To date, no small-molecule inhibitors targeting the PD-1/PD-L1 pathway has been approved for cancer treatment and only one small-molecule inhibitor, the previously mentioned CA-170, has entered a phase I clinical trial in patients with advanced solid tumors and lymphomas [137].” Further, it does not appear that any small-molecule inhibitors of CTLA-4 have been approved or are in late clinical trials as a treatment. The assessment of Lin et al. for small-molecule immune checkpoint inhibitors is in agreement with that of Chen et al. (Eur. J. Med. Chem, 161:378-398, 2019, p. 395, col. 2, first full paragraph), which says, “Currently, the development of small-molecular inhibitors lags far behind antibody drugs. The lack of target structure information restricted the reasonable design of small molecule inhibitors targeting PD-1/PD-L1 pathway. PD-1/PD-L1 interaction is a protein-protein interaction with a large interaction surface and few conventional small molecule binding pockets. In order to discover hot spots on this paired protein, a more detailed analysis of target structures needs to be carried out.” Further (p. 395, third full paragraph), “Researches on small molecule inhibitors targeting the PD-1/PD-L1 pathway is still in the early stage, but it has good prospects…. However, there are still problems to be resolved.”
The Written Description Guidelines for Examination of Patent Applications (MPEP § 2163) indicates, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus…." [See MPEP § 2163(II)(A)(3)(a)(ii)] The claim is drawn to a method of treating by administering an anti-CCR-8 antibody as defined in 12 and an antibody or small molecule targeting and/or inhibiting a checkpoint protein. While the prior art and specification disclose at least 8 anti-checkpoint antibodies meeting the limitations of the claims, there is no disclosure in the prior art or specification of a representative number of small molecules targeting and/or inhibiting a checkpoint protein that would reasonably have been expected to function as needed in the claimed methods of treating. The specification does not place any structure and/or chemical limitations on the small molecule and no structure-function correlation has been established to support a genus of small molecules that not only meet the direct functional limitation but also would be beneficial in the method of treatment claimed. There is no disclosure of any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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 [he or she] invented what is claimed.” (See Vas-Cath at page 1116). Therefore, only an antibody targeting and/or inhibiting a checkpoint protein, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112(a) is severable from its enablement provision (see page 1115).
Claims 16, 18, 27, 31, 32, 38-41 and 45 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 by administering an effective amount of an antagonistic anti-CCR8 antibody or antigen-binding fragment thereof wherein the antibody binds the tyrosine rich domain (TRD) comprising sulfated tyrosine residues of CCR8, does not reasonably provide enablement for wherein treatment is of a disease that is not a tumor, or wherein the antibody is not antagonistic and does not bind the TRD of CCR8 comprising sulfated tyrosine residues. 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).
Each of claims 16, 18, 27 and 31 is like an independent method claim, slightly different one from another. Note that claims 16, 18 and 27 depend from claim 12, but are different inventions (methods of treatment, wherein claim 12 is drawn to an antibody). For all the claims, there is an issue of the scope of enablement of the antibody or antigen-binding fragment thereof that is administered. Claims 16 and 27 are drawn to a method of treating a tumor or disease characterized by the involvement of cells expressing CCR8 (as elected) comprising administering a therapeutically effective amount of the antibody…to a patient in need thereof, …. For these claims the second issue of enablement in particular deals with a disease characterized by the involvement of cells expressing CCR8. The specification has not taught other non-tumor diseases which may be treated with the anti-CCR8 antibody with a reasonable expectation of success. It is not clear what the “involvement of cells expressing CCR8” entails, e.g., does the involvement need to be direct or does it coincide with a particular level of CCR8 expression? Claim 18 is drawn to treating a subject having a tumor that is sensitive for [to] treatment with the anti-CCR8 antibody… by administering a therapeutically effective amount of the anti-CCR8 antibody. In claim 18, the subject is being treated with the antibody. While the treatment could be for the tumor, the claim is not restricted to that. As a result, the skilled artisan would not know what a therapeutically effective amount of anti-CCR8 antibody is for other diseases or conditions that the subject being treated has. Finally, claim 31, like claim 18, is drawn to treatment of the subject and not, in this case, the tumor that is sensitive to treatment with an anti-CCR8 antibody…comprising… administering to the subject a therapeutically effective amount of an anti-CCR8 antibody….
There is no CCR8 (as elected) antibody recited in the claims that bind a first sulfated polypeptide which comprises the TRD of a seven transmembrane receptor, and optionally its LID domain, wherein at least 25% of the tyrosine residues of the TRD are sulfated. The specification discloses a limited group of antibodies that meet the limitations of claim 12. 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 Tregs, but can also be used in other diseases characterized by an aberrant presence of activated, i.e. CCR8 expressing Tregs.” Nor is an “aberrant presence” defined such that the skilled artisan could have a reasonable expectation of predicting which diseases have said aberrant presence of activated CCR8-expressing Treg cells. There are no other diseases besides cancers/tumors that the skilled artisan would reasonably expect to be treatable by administration of the antibody of the claims.
The role of CCR8 in the body is complex as discussed by Trebst et al. (Am. J. Pathol. 162(2):427-436, Feb. 2003, p. 436, col. 2, second paragraph), saying that even though CCR8 is found in association with certain pathologies, such as cerebral ischemia and PML, it appears that the macrophages expressing CCR8 are clearing debris. This is in contrast to the situation in multiple sclerosis, in which it appears CCR8-expressing macrophages are actively stripping myelin from axons. “Expression of chemokine receptors on the cell surface is a result of a complex interplay of regulatory mechanisms including cytokine-regulated transcription and ligand-induced internalization, occurring in the context of differentiation of receptor-bearing cells.” (p. 436, col. 2, start of third paragraph) It appears that CCR8 expression is involved in the central nervous system’s defense against protozoal pathogens (p. 437, col. 1, first paragraph). These examples highlight the complex role of CCR8 expression in disease and that its expression can have a positive or negative impact. The specification does not discuss particular diseases other than tumors that can be treated by administration of the instant antibodies. Therefore, the specification does not enable the full scope of treatment as currently set forth in the claims.
The specification discusses that systemic removal of Treg cells can have negative effects, such as described on p. 252, lines 8-11, leading to increased and/or unregulated autoimmunity. Also, even though CCR8 expression has been implicated in certain CCR8-associated diseases, antagonism of CCR8 is not necessarily sufficient for treatment. For example, CCR8 has been implicated in pathogenesis in asthma mouse models and CCR8 is elevated in human patients with asthma (Wang et al., Thorax. 68:506-512, 2013, “Background” of ABSTRACT, and p. 506, col. 2, start of second paragraph). Wang et al. (ibid., paragraph bridging pp. 506-507) shows that inhibition of CCR8 by a small molecule CCR8-antagonist in a primate asthma model (>98% target inhibition on circulating T-cells) did not lead to significant reduction of lung inflammation, Th2 cytokine production, mucus hypersecretion or changes in lung function induced by inhaled allergen. “Our data suggest that CCR8 antagonism was ineffective in ameliorating allergic airway disease and do not support CCR8 inhibition as a promising strategy for the treatment of atopic asthma.” (p. 507, col. 1, end of first paragraph). Further, Barsheshet et al. (Proc. Natl. Acad. Sci, 114(23):6086-91, 2017, cited in the IDS filed 5/16/2024, p. first sentence of abstract) acknowledges that CCR8* Tregs are “drivers of immunosuppression.” It is theorized that reduced CCR8* Treg activity/numbers is likely to contribute to a variety of diseases, e.g., autoimmune-related. It does not reasonably appear that an antagonistic antibody, of which most of the disclosed antibodies are (p.119, lines 5-6) without further activity would be able to treat asthma. The only teachings in the prior art related to treatment with a CCR8-affecting molecule are drawn to treating tumors by depletion of CCR8-expressing tumor infiltrating Treg cells (e.g., Dépis et al., Canc. Res., 80(16) Suppl. Abst. 4532, 2020, cited in the IDS filed 5/16/2024). This is consistent with instant Example 12.1.1, which characterizes the mode-of-action of surrogate antibodies binding to mouse CCR8 demonstrating antitumor efficacy as being “Treg depletion” depending on ADCC (antibody-dependent cellular cytotoxicity) and/or ADCP (antibody-dependent cellular phagocytosis) (p. 259, lines 3-5, and p. 264, lines 10-11).
Therefore, for the reasons discussed above and including the breadth of diseases encompassed by "involvement of cells expressing CCR8,” the support by the prior art of the complexity and unpredictability of treatment of a disease which is not a tumor, the breadth of anti-CCR8 antibodies encompassed by the claims including those which are not antagonists, the working examples drawn only to treatment of tumors and the only disclosed mechanism of treatment being depletion of Tregs, and the information in the specification and prior art related to the positive impact of the involvement of CCR8-expressing Tregs in suppression of certain pathologies, e.g., autoimmune-originating, it would require undue experimentation to make and use the invention commensurate in scope with the claims.
Claims 16, 18, 27, 31, 32, 38-40 and 45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The methods of claims of 16, 18 and 27 depend from claim 12, wherein claim 12 is drawn to an antibody that specifically binds a first isolated sulfated polypeptide which comprises the tyrosine rich domain (TRD) of a seven transmembrane receptor (CCR8 as elected), and optionally its LID domain, wherein at least 25 %, at least 50 % or at least 75 % of the tyrosine residues of the TRD are sulfated. Claim 31 does not depend from claim 12 and merely requires administration of an “anti-CCR8 antibody or antigen-binding fragment thereof.” The claims have no structural limitations for the anti-CCR8 antibody used in the methods. The antibody is being described only by function.
For the anti-CCR8 antibody 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 discloses a limited group of antibodies that meet the limitations of claim 12 (Tables 7.2.a and 7.2.b). 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. One skilled in the art could not readily envision the structures of a representative number of species of the genus of CCR8-binding antibodies that meet the functional requirements of 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).
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.
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., for claims dependent on claim 12, specific binding to the TRD of CCR8, which TRD is at least 20% suflated, and for all claims 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. Note as discussed above that the instant specification repeatedly refers to the difficulty of obtaining antibodies the specifically bind and inhibit CCR8 in a manner that is suitable for antitutmor therapy.
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.
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)(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) 16 and 27 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]). The antibody may be administered in conjunction with another anti-cancer treatment, including an inhibitory immune checkpoint blocker or inhibitor such as PD-1 or PD-L1 ([0331], [0337], [0339]) ([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 ([0703]). 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 specifically bound a sulfated polypeptide comprising a tyrosine rich domain (TRD) of CCR8.
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) 16, 18, 27, 31, 32, 38 and 39/are rejected under 35 U.S.C. 103 as being unpatentable over US 20210277129 Al (McGrath, cited in the IDS filed 5/16/20204) as applied to claims 16 and 27 above, and further in view of Juneja et al. (J. Exp. Med., 214(4):895-904, 2017).
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]). The antibody may be administered in conjunction with another anti-cancer treatment, including an inhibitory immune checkpoint blocker or inhibitor such as PD-1 or PD-L1 ([0331], [0337], [0339]) ([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 ([0703]). 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 specifically bound a sulfated polypeptide comprising a tyrosine rich domain (TRD) of CCR8.
Juneja et al. showed that MC38 tumor cells express PD-L1, and that PD-1 expression on TILs from MC38 tumors was rapidly up-regulated with T cell activation (p. 896, col. 1, second paragraph, and p. 898, end of col. 2). Administration of an anti-PD-L1 blocking antibody to mice with MC38 tumor cells resulted in tumor clearance in most mice (p. 899, col. 2, first paragraph). It is stated that PD-L1 expression on tumors can correlate with a higher response frequency to PD-l blockade in the clinic (p. 901, sentence bridging cols. 1-2). It is concluded (p. 902, col. 1, end of first full paragraph), “[P]atients whose tumors express high levels and percentages of PD-L1 are more sensitive to PD-1 blockade: tumor PD-L1 may render CD8+ TILs sensitive to PD-1 signaling, which can then be blocked therapeutically. Together, our work demonstrates that PD-L1 on tumor cells can exert functionally significant suppressive effects that inhibit antitumor immunity, and is far more than a marker of an ineffective immune response.” Further, it is reported that (p. 895, col. 1, first paragraph), “PD-1 is commonly highly expressed on tumor-infiltrating lymphocytes (TILs; Ahmadzadeh et al., 2009). Blocking the interaction of PD-1 with its ligands, PD-L1 and PD-L2, leads to impressive antitumor responses and clinical benefit in a subset of patients (Ribas, 2012; Alme et al., 2016).” It is noted that the understanding that the PD-1 pathway is responsible for dampening effector T cell responses and inhibiting the initial activation of T cells. Also, “tumors often express PD-1 ligands.” This knowledge provided the rationale for targeting the PD-1 pathway for antitumor therapy (p. 895, paragraph bridging cols. 1-2).
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant application to have treated a tumor with an anti-CCR8 antibody, especially antibody 7-B16, as taught by McGrath. It further would have been obvious based on the teachings of Juneja et al. relating to the expression of PD-1 ligands, and especially PD-L1 on tumor cells and the successful use of PD-1/PD-L1 inhibitors in the treatment of cancers, to have treated tumors with an anti-CCR8 antibody, especially antibody 7-B16, and to include an immune checkpoint inhibitor antibody, e.g., an anti-PD-L1 antibody as taught by McGrath, particularly after determining that the tumor expressed PD-L1 by comparing the level of PD-L1 in a tumor sample to a reference control. Juneja et al. taught that tumors expressing high levels and percentages of PD-L1 are more sensitive to PD-1 blockade. As a result, it would have been both obvious and desirable to the artisan of ordinary skill to determine the likelihood of effectiveness of antitumor treatment with a PD-1/PD-L1 inhibitor by looking at the biomarker’s presence in the tumor microenvironment.
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 16, 18, 27, 31, 32, 38 and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12,065,497 (‘497) in view of US 2021/0277129 A1 (McGrath).
Both instant claims 16, 18, 27 and 31 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. The antibodies of the patent claims were identified by binding a sulfated tyrosine rich domain (TRD) of CCR8 (the sequences of the antibodies are an inherent property thereof (see, Examples 6 and 7 for support). The species of antibodies used in the method of the patent anticipate the genus of the instant claims. Claims 2-4 of ‘497 recite treatment and also include administration of a PD-L1 targeting agent, specifically an anti-PD-L1 antibody. The claims of ‘497 do not recite use of a biomarker (instant claims 18 and 31).
Lin et al. teach that PD-L1 expression appears to be a predictive biomarker for non-small cell lung cancer (NSCLC) based on disease stage (advanced v. resectable), and the presence of tumor infiltrating lymphocytes (TILs) positively correlates with PD-L1 expression (p. 83992, col. 1, second paragraph, and 83991, col. 1, second paragraph). The expression appeared to be linked to disease stage (p. 83990, col. 2, first paragraph). The use of an anti-PD-L1 biomarker has regulatory approval for use as a diagnostic indicator for therapeutic use of anti-PD-1 antibody pembrolizumab (p. 83987, col. 1, first paragraph). PD-L1 expression has been found to be associated not only with tumors having TILs in the tumor microenvironment, but also a small fraction of human cancers that do not (p. 83987, col. 1, second paragraph). Also, squamous carcinoma tumors had a strong association with PD-L1 expression (83990, col. 2, first paragraph). PD-L1 expression was determined using an antibody against human PD-L1 (p. 83992, col. 1, fourth paragraph).
It would have been obvious wherein treatment was of a tumor with an anti-CCR8 antibody and PD-L1 inhibitory antibody as set forth in the claims of both applications and additionally to use an anti-PD-L1 antibody as a biomarker to indicate desirability of treatment, wherein increased levels of PD-L1 would have been expected to have been indicative of an advanced stage tumor, e.g., NSCLC, in need to treatment.
Claims 16, 18, 27, 31, 32, 38 and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 6, 8, 13, 14, 16-18 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).
The claims of both applications are drawn to a method of treating a subject, including having a tumor or cancer, by administering an antibody or antigen-binding-fragment thereof that binds CCR8 (especially instant claims 16, 18, 27, 31 and claims 1, 18, 25 of ‘032). The instant method is for treatment of a tumor and with an anti-CCR8 antibody and immune checkpoint inhibitor. 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 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.” Claims 4, 6, 8 and 16 of ‘032 recite treatment also includes administration of a PD-L1 targeting agent, specifically an anti-PD-L1 antibody. The claims of ‘032 do not recite use of a biomarker (instant claims 18 and 31).
Lin et al. teach that PD-L1 expression appears to be a predictive biomarker for non-small cell lung cancer (NSCLC) based on disease stage (advanced v. resectable), and the presence of tumor infiltrating lymphocytes (TILs) positively correlates with PD-L1 expression (p. 83992, col. 1, second paragraph, and 83991, col. 1, second paragraph). The expression appeared to be linked to disease stage (p. 83990, col. 2, first paragraph). The use of an anti-PD-L1 biomarker has regulatory approval for use as a diagnostic indicator for therapeutic use of anti-PD-1 antibody pembrolizumab (p. 83987, col. 1, first paragraph). PD-L1 expression has been found to be associated not only with tumors having TILs in the tumor microenvironment, but also a small fraction of human cancers that do not (p. 83987, col. 1, second paragraph). Also, squamous carcinoma tumors had a strong association with PD-L1 expression (83990, col. 2, first paragraph). PD-L1 expression was determined using an antibody against human PD-L1 (p. 83992, col. 1, fourth paragraph).
It would have been obvious wherein treatment was of a tumor with an anti-CCR8 antibody and PD-L1 inhibitory antibody as set forth in the claims of both applications and additionally to use an anti-PD-L1 antibody as a biomarker to indicate desirability of treatment, wherein increased levels of PD-L1 would have been expected to have been indicative of an advanced stage tumor, e.g., NSCLC, in need to treatment.
This is a provisional nonstatutory double patenting rejection.
Claims 16, 18, 31, 32 and 38-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17, 24, 31, 33, 38, 40, 42, 43, 45, 48, 51 and 53 of copending Application No. 18/666,512 (‘512) in view of US 2021/0277129 A1 (McGrath) in light of Campbell et al. (Canc. Res. 81(11):2983-2994, 01 June 2021) and Lin et al. (Oncotarget, 8(48):83986-83994, 2017).
Both the instant claims 16, 18 and 31 and claims 17 and 42 of ’512 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 instant claim 12, which the method claims depend from, and claims 40 and 53 of ‘512) The claims of ‘512 do not recite determining the level of a biomarker (PD-L1 as elected), while instant claims 18 and 31.
Lin et al. teach that PD-L1 expression appears to be a predictive biomarker for non-small cell lung cancer (NSCLC) based on disease stage (advanced v. resectable), and the presence of tumor infiltrating lymphocytes (TILs) positively correlates with PD-L1 expression (p. 83992, col. 1, second paragraph, and 83991, col. 1, second paragraph). The expression appeared to be linked to disease stage (p. 83990, col. 2, first paragraph). The use of an anti-PD-L1 biomarker has regulatory approval for use as a diagnostic indicator for therapeutic use of anti-PD-1 antibody pembrolizumab (p. 83987, col. 1, first paragraph). PD-L1 expression has been found to be associated not only with tumors having TILs in the tumor microenvironment, but also a small fraction of human cancers that do not (p. 83987, col. 1, second paragraph). Also, squamous carcinoma tumors had a strong association with PD-L1 expression (83990, col. 2, first paragraph). PD-L1 expression was determined using an antibody against human PD-L1 (p. 83992, col. 1, fourth paragraph).
It would have been obvious wherein treatment was of a tumor with an anti-CCR8 antibody as set forth in the claims of both applications and additionally to use an anti-PD-L1 antibody as a biomarker to indicate desirability of treatment, wherein increased levels of PD-L1 would have been expected to have been indicative of an advanced stage tumor, e.g., NSCLC, in need to treatment.
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.
US 2019/0071508 A1 teaches treatment of cancer, including in syngeneic mouse models of osteosarcoma (LM8), breast (EMT6) and colorectal (Colon26) cancers (Fig. 29, 31, 32 and 34) with antibodies against CCR8 and optionally in combination with antibodies targeting immune checkpoint proteins, such as PD-1 and PD-L1 ([0047]-[0048] and Examples 261-262). This reference shows the obviousness of including an antibody targeting a checkpoint inhibitor in combination with an anti-CCR8 antibody, however, it is unclear if the antibody of the reference binds a sulfated TRD of CCR8.
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 5/16/2024) 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