DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 2, 10, 22, 26, 28, 43, 49, 75, 88, 99, 103, 107, 121, 132-134, 136-138, 140, 143, 154, 158, 163, 175, 195 and 199-201 are pending.
Election/Restrictions
Applicants' election without traverse of Invention I, claims 2, 10, 22, 26, 28, 43, 49, 75, 88, 99, 103, 107, 121, 137-138 and 140, in the reply filed on 12/4/25 is acknowledged. It is noted that in the restriction requirement mailed on 10/8/25, claim 136 was inadvertently included in the list of claims corresponding to Invention I, despite the subject matter of the claim (“a method comprising using such host cell to produce the encoded antibody”) being listed as part of Invention II. As such, for the record, claim 136 is herewith placed with Invention II.
Claims 132-134, 136, 143, 154, 158, 163, 175, 195 and 199-201 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Three species elections were also required. Applicants indicate the following elections:
(1) an antibody comprising the HCVR/LCVR pair of SEQ ID NO: 72/65 as the species of antibody;
(2) rheumatoid arthritis as the species of rheumatological disease; ulcerative colitis as the species of gastrointestinal disease; idiopathic pulmonary fibrosis as the pulmonary fibrosis; non-alcoholic steatohepatitis as the hepatological disease; diabetic kidney disease as the nephrological disease; atopic dermatitis as the dermatological disease; and lupus of the skin as the immune skin disease or condition; and
(3) methotrexate, infliximab, corticosteroid, metformin, topical corticosteroid, and acetyl CoA carboxylase inhibitors as the species of first additional therapeutic.
With respect to the first election of species, the election of the antibody is acknowledged. However, for the second and third elections of species, Applicants reply is not sufficient to elect a single species. As stated on page 5, Applicants are required to elect “a single disclosed species” of “(2) disease or condition” and “(3) first additional therapeutic”. As such, Applicants should, in reply to this action, indicated an election of a single disease or condition (e.g., rheumatoid arthritis), and a first additional therapeutic (e.g., methotrexate).
Claims 2, 10, 22, 26, 28, 43, 49, 75, 88, 99, 103, 107, 121, 137-138 and 140 are under consideration.
Specification
The disclosure is objected to because of the following informalities:
The title of the invention is not descriptive because in part it is directed to “Uses Thereof”, but the only use in the claims is for treatment of a disease or condition. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “Engineered CD200R Antibodies and Uses Thereof in Treatment of Disease”.
Appropriate correction is required.
Claim Objections
Claims 2, 10, 22, 26, 28, 43, 49, 75, 88, 99, 103, 107, 121, 137-138 and 140 are objected to because of the following informalities:
In independent claim 2, the abbreviation “CD200R” should be accompanied by the full terminology the first time it appears; e.g., “CD200R (CD200 receptor)”.
In claim 28, line 2, “wherein” should be “wherein:”
In claim 28, element (a), “comprise” should be “comprises”.
In claim 28, in each of element (d)(i) and (d)(ii), the optional recitation in the second half is duplicative because it is directed to elements that are already referred to in the first half of the element. For example, in (d)(i), the second half refers to “SEQ ID NOS: 61, 75, and 76”, which are already referred to in the first half.
In claim 49, line 2, “wherein” should be “wherein:”
In claim 75, element (a)(2), “P238D;” should be “P238D,”
In claim 88, element (a), “of C-terminus” should be “of the C-terminus”, and in element (b), “of N-terminus” should be “of the N-terminus”. Every protein inherently has an N-terminus and a C-terminus, thus it is not indefinite to refer to such with a definite article. See MPEP 2173.05(e): “Inherent components of elements recited have antecedent basis in the recitation of the elements themselves. For example, the limitation "the outer surface of said sphere" would not require an antecedent recitation that the sphere has an outer surface.”
In claim 98, element (f), “KD” should be written “KD”. Compare with element (e).
Throughout claim 121, “KD” should be written “KD”. Compare with claim 98, (e).
Claims 103 and 107 are objected to for referring to examples in the specification; specifically “an assay described in Example 5, 16, or 17” (claim 103), “an assay described in Example 5” (claim 107) and “an assay described in Example 18” (claim 107). This is analogous to referring to a table in the specification, as set forth in MPEP § 2173.05(s), "[w]here possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claims. Incorporation by reference is a necessity doctrine, not for applicant's convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)." In the instant case, the assay described in Examples 5, 16 or 17 can be written out in the claims, and thus, there is a practical way to define the invention in words.
In claim 140, line 3, “an pharmaceutical composition” should be “a pharmaceutical composition”.
In claim 140, line 5, “…comprising a an informational material…” should be “…comprising informational material…”
The remaining claim(s) are objected to for depending from an objected claim.
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.
Claims 2, 10, 22, 26, 28, 43, 49, 75, 88, 99, 103, 107, 121, 137-138 and 140 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 pre-AIA the applicant regards as the invention.
In each of claims 2, 10, 28, 49 and 78, the use of the phrase "such as" 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).
In claim 28, part (d)(i) and (d)(ii) the recitations of “the amino acid sequence as set forth in SEQ ID NOS: 61, 63, 75, and 76” and “the amino acid sequence as set forth in SEQ ID NOS: 61, 76, and 76” are each indefinite because a single amino acid sequence is referred to (“the amino acid sequence”) but then a group of four amino acid sequences joined by “and” are then referred to.
In claim 88, elements (a)-(f) are not joined by a conjunction, and thus it is unclear whether they are recited in the alternative (“or”) or together (“and”) or both (“and/or”).
Claim 107 is indefinite for the following reasons. It recites six elements, (a)-(f), joined by “and/or”, and thus can be individually present or all present together. However, elements (c) and (f) do not stand alone as they recite, “(c) the immune cell is a T cell or a monocyte” and “(f) where said inhibition of activation of basophils is measured in an assay described in Example 18”. Thus, in the alternatives directed to element (c) or element (f) alone, it is unclear what the antibody of the claim is being limited to, as element (c) limits a cell that otherwise has no relation to the antibody and element (f) limits activation of basophils that otherwise has no relation to the antibody. Furthermore, element (c) is also indefinite with respect to the alternative where the elements are joined by “and”, because parts (a) and (b) are each directed to “an immune cell”, and it is unclear which (or both) that part (c) applies to.
Claim 138 is indefinite because, as amended line 3 recites: “…claim 2 an immunoconjugate comprising…”, which appears to be missing a conjunction between the antibody and the kit, rendering it unclear whether the composition comprises both an antibody and an immunoconjugate, or only one of these. If the former in intended, the elements of the composition should be clearly delineated, for example: “A pharmaceutical composition comprising (a) a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 2; or (b) a therapeutically effective amount of an immunoconjugate comprising the antibody or antigen-binding fragment thereof, and wherein the composition comprises at least one pharmaceutically acceptable excipient”.
Claim 140 is indefinite because it is unclear whether the immunoconjugate or pharmaceutical composition are part of the kit or separate alternatives to which the claim is directed. If the former is intended, the elements of the kit should be more clearly delineated, for example: “A kit comprising (a) the antibody or antigen-binding fragment thereof of claim 2; (b) an immunoconjugate comprising the antibody or antigen-binding fragment thereof; or (c) a pharmaceutical composition comprising the antibody, antigen-binding-fragment thereof, or the immunoconjugate in a container; optionally wherein the kit further comprises informational material containing instructions.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
Claim Rejections - 35 USC § 112(a), written description
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 2, 10, 22, 26, 28, 43, 49, 75, 88, 99, 103, 107, 121, 137-138 and 140 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The claims are directed to a product; specifically, an antibody, or antigen-binding fragment thereof, that specifically binds to the protein CD200R, which is an immune cell receptor for the protein CD200. The specification at page 69 teaches:
“CD200 is a member of the immunoglobulin superfamily (IgSF) and a transmembrane type 1 a glycoprotein and can be highly expressed in a variety of cells types, for example, dendritic cells, macrophages, B lymphocytes, neuronal and endothelial cells, as well as in some T lymphocytes. CD200 has been implicated in inhibitory signaling which prohibits or reduces expression of genes involved in inflammatory responses. CD200 can function in concert with its natural receptor CD200R to activate the immunosuppression signaling cascade”
In addition to being defined by its functionality, i.e., binding to CD200R, the claimed antibody is defined structurally as having two chains, heavy and light, each with variable regions comprising complementarity-determining regions (CDRs) defined by similarity to amino acid sequences disclosed in the specification by SEQ ID NO. More specifically, independent claim 2 recites a group of 9 different sets of heavy chain CDRS (HCDRs1-3) from which the heavy chain CDRs can be selected, and a group of 7 different sets of light chain CDRs (LCDRs1-3) from which the heavy chain CDRs can be selected. These CDRs correspond to antibodies disclosed in Table 1 of the specification, including clones 21.3.1 (HCDRs/LCDRs of SEQ ID NO: 3-5/6-8); 26.1.2 (SEQ ID NO: 11-13/14-16); 2.2.7 (SEQ ID NO: 19-21/22-24); 3.10.2 (SEQ ID NO: 27-29/30-32); 7.12.2 (SEQ ID NO: 35-37/38-40); Table 8, including antibody hu2131, which is a humanized version of 21.3.1 (SEQ ID NO: 3, 41, 5/6, 67, 8) and Table 9, including antibody hu2131_Q1E (SEQ ID NO: 3, 41, 70/6, 67, 8). The sets also include a version in which CDRH1 is SEQ ID NO: 92, which is SEQ ID NO: 3 with an W or F at position 3; and version where CDRH3 is SEQ ID NO: 69, which is SEQ ID NO: 70, where position 1 is M or G.
The specification provides evidence that clones 21.3.1, 26.1.2, 2.2.7, 3.10.2 and 7.12.2 are functional in binding to human and cynomolgus CD200R; see Table 2 on page 398. The variants of 21.3.1, including hu2131 and hu2131_QE were also demonstrated to bind CD200R; see Table 7 on pages 404-405 and Table 11 on page 408. As such, the specification provides written description for antibodies having each defined set of six CDRs demonstrated to have functionality in binding to CD200R. However, the claims are not limited to these six sets, and instead encompass variation in the following two ways: (1) the claims are not limited to complementary sets of three HCDRs and three LCDRs from one of the tested antibody, but instead encompass any set of three HCDRs from the tested antibody with any set of three LCDRs; and (2) the claims are not limited to antibodies having the defined CDR sequences, but instead encompass variants in which up to 3 amino acids are changed in each of the six CDRs of an antibody. A number of CDRs, such as SEQ ID: 5, 29 and 37, are only 5 amino acids in length, with 3 amino acids representing 60% of the CDR. Other CDRs are longer, such as 9 or 10 amino acids, but the variants still include those in which 30-33% of the CDRs are changed.
While the general structure of an antibody was well-known in the prior art, it is the structure of the complementarity-determining regions (CDRs) that determines the specificity of a particular antibody, and said CDR structure is not predictable based on the epitope to which it binds. Thus, even knowing the structure (CDRs) of one antibody does not allow the skilled artisan to predict the full extant of amino acids that can be made that will retain binding to the same epitope in the same target protein. The relevant art, Ferrara et al (2015. mAbs. 7(1): 32-41) teaches that there is substantial variation in the structure of antibodies that bind to a single protein, on the order of hundreds of different sequences; specifically, see page 36: "The number of different HCDR3s selected against the test antigens ranges from 74 to 460 (Table 3), with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (pg 36).
The decision of the Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target protein (e.g., CD200R) itself is not sufficient to provide a written description of the genus of antibodies binding to said target protein. Furthermore, a genus of antibodies defined by function, e.g., binding CD200R, is not sufficient to describe the genus because such a definition only indicates what the antibody does, rather than what it is; i.e., the specific structure of the antibody. It is only a definition of a useful result rather than a definition of what achieves that result. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition". Furthermore, in the instant case the specification does not establish a correlation between structure and function, which means the structures of the various CD200R antibodies is not predictable based on the disclosed function.
Thus, in the instant case, written description of the variants of the disclosed anti-CD200R antibodies to be used in the claimed method must be satisfied through sufficient description of a relevant number of species encompassed by the genus. However, in contrast to the scope of the variants of the claimed anti-CD200R, the instant specification provides only limited examples that are directed to the clones and variants thereof that were tested as described in the working examples. These limited examples are not sufficient to described the genus of variant anti-CD200R antibodies encompassed by the claims, because such is not representative of the full scope of what is encompassed; i.e., (1) variants with different combinations of sets of HCDRs and sets of LCDRs, and (2) variants with up to 3 amino acids changed in each of the six CDRs of the antibody. Per MPEP 2163, "A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
MPEP 2163 provides guidance for complying with the written description requirement of 35 U.S.C. 112(a) that the “specification shall contain a written description of the invention…”; this requirement is separate and distinct from the enablement requirement (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). Written description for a claimed genus may be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Written description for a claimed genus can also be satisfied when relevant identifying characteristics are disclosed. Per MPEP 2163, “[d]etermine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.” However, claiming by function does not necessarily satisfy the written description requirement. “[A] generic statement such as "vertebrate insulin cDNA" or "mammalian insulin cDNA," without more, is not an adequate written description of the genus because it does not distinguish the claimed genus from others, except by function. It does not specifically define any of the genes that fall within its definition. It does not define any structural features commonly possessed by members of the genus that distinguish them from others … A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. It is only a definition of a useful result rather than a definition of what achieves that result” (Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). Also, “[w]hen 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 result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)), and “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “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” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of anti-CD200R 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. The compound itself is required. 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). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, with respect to the elected invention under consideration, only an antibody, or an antigen-binding fragment thereof, that specifically binds CD200R (CD200 receptor), comprising:
a heavy chain (HC) comprising a HC variable region (HCVR) comprising CDRH1-3 comprising SEQ ID NO: 3 or 92; 41; and 70, 69 or 5; and a light chain comprising a LC variable region (LCVR) comprising CDRL1-3 comprising SEQ ID NO: 6, 67 or 68 and 8;
a HC comprising a HCVR comprising CDRH1-3 comprising SEQ ID NO: 3-5; and a LC comprising a LCVR comprising CDRL1-3 comprising SEQ ID NO: 6-8;
a HC comprising a HCVR comprising CDRH1-3 comprising SEQ ID NO: 11-13; and a LC comprising a LCVR comprising CDRL1-3 comprising SEQ ID NO: 14-16;
a HC comprising a HCVR comprising CDRH1-3 comprising SEQ ID NO: 27-29; and CDRL1-3 comprising SEQ ID NO: 30-32;
a HC comprising a HCVR comprising CDRH1-3 comprising SEQ ID NO: 35-37; and a LC comprising a LCVR comprising CDRL1-3 comprising SEQ ID NO: 38-40,
but not the full breadth of the claims meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Patentability
No prior art has been identified that teaches or suggests an antibody, or an antigen-binding fragment thereof, that specifically binds CD200R (CD200 receptor), comprising a heavy chain (HC) comprising a HC variable region (HCVR) comprising CDRH1-3 comprising SEQ ID NO: 3; 41; and 70, 69 or 5; SEQ ID NO: 11-13; SEQ ID NO: 19-21; SEQ ID NO: 27-29; SEQ ID NO: 35-37; or SEQ ID NO: 92, 41 and 69; and a light chain (LC) comprising a LCVR comprising CDRL1-3 comprising SEQ ID NO: 6; 67, 7 or 68; and 8; SEQ ID NO: 14-16; SEQ ID NO: 22-24; SEQ ID NO: 30-32 or SEQ ID NO: 38-40.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674