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 .
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 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.
Priority
The instant application, filed 06/09/2023, claims domestic benefit to US provisional applications 63/385,877, filed 12/02/2022, and 63/351,282, filed 06/10/2022.
Status of Application, Amendments, and/or Claims
Applicant’s response of 08/11/2026 is acknowledged. Claims 1-9, 11-13, 15, 17, 26, 47, 51-52, and 63 are amended and claims 21-24, 53-55, 57-58, 60-62, 64-65, 68-77, and 79-81 are cancelled.
Applicant’s supplemental amendment of 09/08/2026 is also acknowledged and is entered. Claims 1 and 40 were amended and claims 21-24, 53-55, 57-58, 60-62, 64-65, 68-77, and 79-81 are cancelled.
Claims 1-20, 25-52, 56, 59, 63, 66-67, 78, and 82 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 01/30/2026,
The sequence disclosure was objected to. Applicant’s amendments to the specification to provide the SEQ ID NOs for Figs. 7 and 11 and the sequences in [00209] has overcome the objection and the objection is withdrawn. Additionally, applicant’s argument concerning LALAPG in [00222] being an art recognized name for L234A, L235A, P329G mutations is persuasive, and the objection is withdrawn.
Claims 1-9, 11-13, 15, 17, and 26 were rejected under 35 USC 112(b) for including the substituted amino acid in parentheticals. Claims 10, 14, 16-25, 27-56, 59, 63, 66-67, 78, and 82 were rejected by virtue of their dependency on the rejected claims. Applicant’s amendments to the claims to remove the parentheticals has overcome the rejections and the rejections are withdrawn.
Claim 1 was rejected under 35 USC 112(b) and claims 2-56, 59, 63, 66-67, 78, and 82 were rejected by virtue of their dependency on claim 1. Applicant’s amendment to claim 1 to remove recitation of position 237 has overcome the rejections and the rejections are withdrawn.
Claim 8 was rejected under 35 USC 112(b) and claims 9-10 were rejected by virtue of their dependency on claim 8. Applicant’s amendment to claim 8 to remove recitation of position 327 has overcome the rejections and the rejections are withdrawn.
Claims 53-55 were rejected under 35 USC 112(b). The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claim 47 was rejected under 35 USC 112(b). Applicant’s amendment to remove “or antibody” has overcome the rejection and the rejection is withdrawn.
Claim 63 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to change dependency to claim 59 has overcome the rejection and the rejection is withdrawn.
Claims 21-24 and 53-55 were rejected under 35 USC 112(a) and 35 USC 103. The cancelation of the claims has rendered the rejections moot and the rejections are withdrawn.
The following grounds of objections and/or rejections are new, maintained, or modified as required by applicant’s amendment to the claims.
Specification Objection
The use of the term “NANOBODY™”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The instant specification recites “nanobody” on page 7 in the fourth line from the bottom of [0011]). The term “NANOBODY” is a trademark and should be capitalized anywhere that it appears and/or include an appropriate symbol, such as ™. The term should also be accompanied by generic terminology.
Response to Arguments
Applicant’s arguments concerning the specification objection in the response filed 07/29/2026 have been fully considered but are not persuasive.
Applicant argues that one of ordinary skill in the art would appreciate that “nanobody” generically refers to the antigen binding fragment from a heavy chain antibody and is currently not a relevant registered trademark. Applicant argues that the scientific literature commonly refers to “nanobody” without indicating or referring to any trademarked product or company. Applicant argues that “nanobody” has been the generic term in the relevant scientific literature for many years and cites MPEP 2173 as allowing applicants to be their own lexicographers.
While it is appreciated that the term “NANOBODY™” may be commonly referred to in the literature, and may appear to be a generic term in the scientific literature, the term is still a registered trademark.
MPEP 2173, which is cited by applicant in the response, states “A fundamental principle contained in 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph is that applicants are their own lexicographers. They can define in the claims what the inventor or a joint inventor regards as the invention essentially in whatever terms they choose so long as any special meaning assigned to a term is clearly set forth in the specification.”
The use of “NANOBODY™” in the specification, however, is not applicant acting as their own lexicographer nor does the specification provide any definition or special meaning to the term. The specification does not provide any definition for “NANOBODY™”. It is also noted that in the response, applicant identifies “NANOBODY™” as a binding fragment from a heavy chain antibody, which is the art recognized definition of the registered trademark.
Claim Objection
Claim 1 is objected to for the following informality: line 4 of the claim recites “234and 235”. Correction to the recitation to add a space between “234” and “and” is suggested.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20, 25-52, 56, 59, 63, 66-67, 78, and 82 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 1-9, 11-13, 15, 17, 25-27, 40, and 43-44 are drawn to a polypeptide comprising a mutant or variant human IgG Fc domain capable of binding FcγRIIb, where the mutant or variant human IgG Fc domain comprises the recited substitution mutations with amino acid position numbering according to the EU index. However, there is insufficient antecedent basis for the recited positions as the claim(s) do not recite a parent sequence to which the positions recited could be referring to, rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
Claims 10, 14, 16, 18-20, 28-39, 41-42, 45-52, 56, 59, 63, 66-67, 78, and 82 are rejected by virtue of their dependency on a rejected claim as they do not resolve the ambiguity discussed above.
In the instant office action, the claims are interpreted as referencing the wild-type Fc of instant SEQ ID NO: 1.
Claim 50 contains the trademark/trade name “NANOBODY™”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular product and, accordingly, the identification/description is indefinite.
Response to Arguments
Applicant’s arguments concerning the rejections under 35 USC 112(b) above in the response filed 07/29/2026 have been fully considered but are not persuasive.
With regards to the rejections of claims 1-9, 11-13, 15, 17, 25-27, 40, and 43-44 specifically, applicant argues that the Kabat numbering system refers to specific positions in antibodies and the system is a standard reference system in the antibody/immunology field. Applicant also agrees that SEQ ID NO: 1 refers to the wild-type sequence.
The rejection of record, however, is not concerning the Kabat numbering system/EU index or whether or not one of ordinary skill in the art would be capable of using these numbering system to identify amino acid positions in a particular sequence. Rather, the rejection is concerned with the lack of recitation of a parent sequence in the claims. As no parent sequence is recited, there is no antecedent basis for the positions recited in the claims. Although applicant agrees with the interpretation that SEQ ID NO: 1 is the wild-type sequence, this sequence is not recited in the claim. As there is no parent sequence recited in the claim, there is insufficient antecedence for the positions recited in the claim and the rejection is maintained.
With regards to the rejection of claim 50 for the recitation of the registered trademark “NANOBODY™”, applicant argues that the claim does not refer to a ““NANOBODY™” trademarked product and that one of ordinary skill in the art would understand the term to refer to the antigen binding fragment of a heavy chain antibody. Applicant argues that the scientific literature commonly refers to a “nanobody” without indicating or referring to any trademark product or company. Applicant argues that “NANOBODY™” is not a relevant registered trademark.
These arguments are not persuasive for the reasons discussed above concerning the specification objection.
Furthermore, MPEP 2173.05 (u) states “If the trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph…The claim scope is uncertain since the trademark or trade name cannot be used properly to describe any particular material or product. In fact, the value of a trademark would be lost to the extent that it became the generic name of a product, rather than used as an identification of a source or origin of a product. Thus, the use of a trademark or trade name in a claim to describe a material or product would not only render a claim indefinite, but would also constitute an improper use of the trademark or trade name.”
As discussed above, the term “NANOBODY™” is a registered trademark.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-9, 11-13, 19-20, 25-31, 33-36, 47-52, 56, 59, 63, 66-67, 78, and 82 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015.
US’284 teaches optimized Fc variants, engineering methods for their generation, and their application, particularly for therapeutic purposes (page 1, [0002]).
The Fc region of an antibody interacts with a number of Fc receptors and ligands, imparting an array of important functional capabilities referred to as effector functions. For IgG, the Fc region, as shown in Fig. 1, comprises Ig domains Cγ2 and Cγ3 and the N-terminal hinge leading to Cγ2. An important family of Fc receptors for the IgG class are the Fc gamma receptors (FcγRs). These receptors mediate communication between antibodies and the cellular arm of the immune system. In humans, this family includes FcγRI (CD64), including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including isoforms FcγRIIa (including allotypes H131 and R131), FcγIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2). These receptors typically have an extracellular domain that mediates binding to Fc, a membrane spanning region, and an intracellular domain that may mediate some signaling event within the cell (page 1, [0005]).
US’284 teaches Fc variants that are optimized for a number of therapeutically relevant properties. These Fc variants are generally contained within a variant protein, that preferably comprises an antibody or an Fc fusion protein (page 4, [0019]). The Fc variants, and proteins containing these variants, have at least 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 or more amino acid substitutions compared to the parent Fc polypeptide, for example, the Fc region of SEQ ID NO: 1. The Fc variants exhibit altered Fc ligand binding compared to the parent Fc (page 5, [0021]-[0022]).
US’284, SEQ ID NO: 1 comprises the wild-type Fc parent sequence (instant SEQ ID NO: 1) of the instant application as shown in the ABSS alignment below:
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US’284 teaches that the Fc variants comprise at least one amino acid substitution at a position selected from the group consisting of 221, 222, 223, 224, 225, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 255, 258, 260, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281, 282, 283, 284, 285, 286, 288, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, and 337, wherein the numbering of the residues in the Fc region is that of the EU index as in Kabat (page 4, [0020]). Positions which comprise the position of the substitutions of the instant claims.
US’284 further teaches preferred Fc substitutions in these positions including E333V, S239L, H268P, A327L, L328A, L234, and L235 (pages 4-5, [0020]).
US’284 also teaches the preferred Fc substitutions of T299A, L234P or L234D, L235T or L235F, S267D, I332Q, G236R, G237D, A330H, E333I, and T299L (pages 4-5, [0020]). The IgG Fc region disclosed by US’284 also comprises a serine at position 298 and a threonine at position 299 (SEQ ID NO: 1; pages 4-5, [0020]).
US’284 constructed Fc variants, with each of these substitutions at least individually, and experimentally tested them. Figures 41a-41pp provides the binding data of the variants (page 11, [0077]). US’284 demonstrates that, Fc regions with each of the modifications above were capable of binding to human FcγRIIb.
US’284 further teaches that the Fc domains are aglycosylated or glycosylated (page 7, [0031]; Figure 39).
US’284 further teaches that the modified Fc region is part of an antibody or a Fc fusion (page 3, [0010]). US’284 teaches that the “antibody” is a protein consisting of one or more polypeptides substantially encoded by all or part of the recognized immunoglobulin genes. The term includes full length antibodies and antibody fragment, and may refer to a natural antibody from any organism, an engineered antibody, or an antibody generated recombinantly for experimental, therapeutic, or other purposes as defined. The term “antibody” includes antibody fragments known in the art, including scFv. US’284 further teaches that the antibody can be agonistic (page 11, [0083]). US’284 further teaches that full length antibodies include variable and constant regions. For example, in most mammals, including humans and mice, the full length antibody of the IgG class is a tetramer and consists of two identical pairs of two immunoglobulin chains, each pair having one light and one heavy chain, with each light chain comprising immunoglobulin domains VL (variable light chain domain) and CL (constant light chain domain) and each heavy chain comprising a VH (variable heavy chain domain) and constant regions. In some mammals, for example in camels and llamas, IgG antibodies may consist of only two heavy chains, each heavy chain comprising a variable domain attached to the Fc region (page 11, [0085]), which are single domain antibodies.
US’284 further teaches that virtually any antigen may be targeted by the Fc variants, and provides numerous examples, including CD40, that are non-FcR receptors (page 16, [0113]). US’284 also teaches that the target of the antibody can be soluble or cell surface bound (page 18, [0115]).
US’284 further teaches that the fusion and conjugate partners are Fc polypeptides and that the Fc variant may be a multimeric Fc polypeptide, comprising two or more Fc regions. The advantage of such a molecule is that it provides multiple building sites for Fc receptors with a single protein molecule (page 29, [0169]). US’284 teaches the use of the Fc regions in an oligomer, including a homo- or hetero-oligomer (pages 15-16, [01110]).
US’284 further teaches that effector function can be a problem for radiolabeled antibodies and antibodies conjugated to toxins, referred to as immunotoxins. These drugs can be used to destroy cancer cells, but the recruitment of immune cells via Fc interaction with FcγRs brings healthy immune cells in proximity to the deadly payload, resulting in depletion of normal lymphoid tissue along with targeted cancer cells. This problem can potentially be circumvented by using IgG isotypes that poorly recruit complement or effector cells. An alternative solution is to develop Fc variants that reduce or ablate binding (page 13, [0102]). The Fc variants disclosed may be fused or conjugated to one or more other molecules or polypeptides. Conjugate and fusion partners may be any molecule, including small chemical compounds and polypeptides, including toxins (page 28, [0164]). US’284 further teaches methods of covalently linking the Fc variants to conjugate partners (page 30, [0171]).
US’284 further teaches that the amino acid substitutions are made by generating a nucleic acid that encodes the variant (page 69, claim 28). US’284 teaches a method of making the polypeptide comprising culturing a host cell under conditions where the polypeptide is produced, then purifying said polypeptide (page 69, claim 29).
US’284 further teaches pharmaceutical compositions comprising the Fc variants and physiologically or pharmaceutically acceptable carrier or diluent (page 7, [0035]; page 37, [0210]). US’284 teaches that it is also possible to administer a nucleic acid encoding the Fc variant, for example, by retroviral infection, direct injection, or coating with lipids, cell surface receptors, or other transfection agents (page 38, [0218]).
US’284 further teaches a method of treating a patient in need thereof, said method comprising administering a polypeptide produced according to the methods disclosed (page 69, claim 40). A “patient” includes both humans and other animals, preferably mammals, and can include both human therapy and veterinary applications. The term “treatment” is meant to include therapeutic treatment, as well as prophylactic or suppressive measures for a disease or disorder. For example, successful administration of an Fc variant results in treatment of the disease (page 36, [0202]). As US’284 teaches methods of administering the Fc variants in the form of an antibody to a mammalian subject, US’284 teaches methods of binding proteins in mammalian subjects.
While US’284 does not exemplify the claimed combination of substitution mutations, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to make the claimed substitutions based on the teachings of US’284. It would have been obvious to make these substitutions as US’284 teaches methods of optimizing Fc domains for therapeutic purposes and provides Fc positions at which amino acid modifications can be made to generate optimized Fc variants, including the positions and substitutions of the instantly claimed invention. Additionally, US’284 made Fc variants and experimentally tested binding and provides data on each substitution allowing for modification with a reasonable expectation that the Fc domain will be capable of binding human FcγRIIb, as claimed.
Claims 2, 14, and 28-32 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 as applied to claim 1 above, and in further view of US 2016/0376371 A1 (Ravetch, J., et al) 29 Dec 2016.
US’284 teaches the polypeptide of claim 1 as discussed in detail above.
US’284, however, does not disclose that the Fc domain further comprises a S298 substitution. US’284 also does not explicitly disclose that the antibody is an anti-CD40 agonistic antibody.
US’371 teaches agonistic antibodies, or antigen binding portions thereof, that bind human CD40. Such antibodies optionally comprise Fc regions with enhance specificity for FcγRIIb. US’371 further provides methods of treatment of cancer or chronic infection by administering the antibodies to a subject in need thereof (abstract). US’371 teaches that the antibodies have constant domains with modified Fc regions having enhanced affinity for FcγRIIb as compared with their affinity for other Fc receptors, i.e., activating receptors. Such agonistic anti-CD40 antibodies with enhanced FcγRIIb specificity are expected to exhibit superior efficacy in treatment of cancer and chronic infection. US’371 teaches that such FcγRIIb-specific agonistic anti-CD40 mAbs may exhibit enhanced adjuvant effects by increasing the maturation of dendritic cell promoting expansion and activation of cytotoxic CD8+ T cells, leading to enhanced anti-tumor response. US’371 considers that FcR-mediated signal enhancement of agonistic CD40 antibodies could be due to increased receptor clustering, or crosslinking, of the antibodies contributing to therapeutic efficacy. Cross-linking of CD40 agonistic antibodies by FcR engagement by the Fc portion of the antibody may increase signal strength and thereby enhance activation of the cells (pages 35-36, [0298]).
US’371 teaches that mutations can be introduced to antibodies to restore effector function, for instance to aglycosylated antibodies. US’371 teaches that mutations that can restore FcγR binding include S298G and/or T299 A/G/ or H (page 17, [0142]). US’371 also teaches that the numbering disclosed is according to the EU index in Kabat (page 7, [0053]; page 36, [0300])
US’371 further teaches full-length antibodies comprising VH and VL domains (page 18, [0152]-[0154]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the mutant Fc domain disclosed by US’284 to further include a S298G mutation and to have the antibody be a full-length anti-CD40 agonistic antibody as taught by US’371. An ordinarily skilled artisan would have been motivated to further include the S298G mutation as US’371 teaches that such mutation, in combination with T299A, can restore effector function, increase signal strength, and the activation of cells in an agonistic antibody. It would have been obvious to have the antibody be a full-length anti-CD40 agonistic antibody as US’371 teaches that such antibodies can comprise mutated Fc regions and be used in the treatment of diseases including cancer and chronic infection. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches the mutation T299A, which US’371 teaches the S298G mutation in combination with. Additionally, US’284 teaches that the antibody can be agonistic and also that the target can be CD40 demonstrating a nexus among the art.
Regarding claim 14, as discussed above, US’284 teaches the parent human IgG Fc domain SEQ ID NO: 1. US’284, SEQ ID NO: 1 has the following alignment with instant SEQ ID NO: 3:
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As discussed above, US’284 also teaches modifications that can be made in the Fc domain including E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, T299A, A327L, L328A, A330H, and E333I. As discussed above, US’371 teaches the mutation S298G in combination with T299A to increase FcγRIIa binding and the effector function of agonistic antibodies. These mutations, in the human IgG Fc domain of US’284, SEQ ID NO: 1 would result in a human IgG Fc domain that is identical to instant variant 2b18K of SEQ ID NO: 3.
While the prior art does not exemplify the Fc mutant, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to make a variant human IgG Fc domain in order to optimize binding of FcγR receptors using the modifications disclosed by US’284 and US’371 in the human IgG Fc domain disclosed by US’284. It would have been obvious to use the mutations disclosed by US’284 and US’371 as both references teach the substitutions as those that can be made in Fc regions of antibodies to enhance antibody function. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. The conclusion of prima facie obviousness is further supported by KSR(E) obvious to try. See MPEP 2143. In this case, the combination of applied references teaches a finite number of substitutions that can be made in antibody Fc domains in order to improve functions. The art also provides experimental testing of the substitutions allowing for predictable modifications of the Fc domains. Therefore, one of ordinary skill in the art would have been able to pursue the known, potential solutions with a reasonable expectation of success.
Furthermore, it would have been obvious to an ordinarily skilled artisan to use the human IgG Fc domain and the substitutions disclosed in the prior art as a starting point for optimization that was routine in the art in order to achieve the desired Fc properties.
MPEP 2144.05 (II) A. states "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”.
In this case, the combination of applied references demonstrate that modification to Fc domains were routine in the art as were optimizing properties of the modified Fc domains using amino acid substitutions. Therefore, it would have been obvious to use the substitutions taught in the prior art as a starting point to determine the optimal Fc sequence for a given polypeptide application.
Regarding claims 21-24 and 53-55, the recited limitations are functional properties that are inherent to the amino acid sequence of the mutant Fc domain. As discussed above, the combination of US’284 and US’786 teach a parent domain and substitutions rendering instant SEQ ID NO: 3, or variant 2b18K, obvious. The functional properties recited in claims 21-24 are inherent to this amino acid sequence, as evidenced by the instant disclosure, Table 5 and [00222], and; therefore, would flow naturally from following the suggestions of the prior art. MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Claims 10, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 as applied to claim 1 above, and in further view of US 2016/0376371 A1 (Ravetch, J., et al) 29 Dec 2016, US 2006/0275283 A1 (van Vlijmen, H., et al) 7 Dec 2006, and US 10,851,178 B2 (Bernett, M.J., et al) 1 Dec 2020.
US’284 teaches the polypeptide of claim 1 as discussed in detail above.
As discussed above, US’284 teaches the parent human IgG Fc domain SEQ ID NO: 1. US’284, SEQ ID NO: 1 has the following alignment with instant SEQ ID NO: 2.
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As discussed above, US’284 teaches substitutions of E233V, L324P, L235T, S239L, S267D, H268H, T299A, A327L, L328A, and I332Q.
US’284, however, does not disclose the substitutions of K210E, S298G, or K334V.
The teachings of US’371 are as discussed above and, as discussed above, US’371 teaches the modification of S298G.
US’283 teaches the altering of effector functions mediated by an Fc-containing polypeptide by modifying one or more amino acid residues within the polypeptide. The polypeptides produced by the method are highly variable and can include antibodies and fusion proteins that contain an Fc region or a biological portion thereof (abstract).
US’283 teaches a substitution at position 334, including K334V (page 3, [0065]; Page 5, [0151]). US’283 also provides data regarding the K334V mutation in a bridging assay with human FcγRIIb (CD32b) (page 5, [0151]; Fig. 4).
US’178 teaches engineered variants of constant regions and studied the impact of charge state on antibody pharmacokinetics in novel engineered variants in the constant regions to improve half-life (col. 2, lines 26-30). US’178 teaches numerous IgG variants that comprise the K210E substitution. For instance, see SEQ ID NOs: 7, 11, 25-28, 35, 38, 41, 44, 47, 52-53, 57, and 68-70.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the human IgG Fc domain disclosed by US’284 to further comprise a mutation of S298G as disclosed by US’371, to further include a K334V mutation as disclosed by US’283 and a K210E substitution as disclosed by US’178. It would have been obvious to include these mutations as the prior art demonstrates that they were known substitutions that could be made in Fc regions in order to optimize effector function. An ordinarily skilled artisan would have had a reasonable expectation of success as all of US’284, US’371, US’283, and US’178 teach methods of modifying IgG Fc regions in order to optimize Fc effector functions. The conclusion of prima facie obviousness is further supported by KSR(E) obvious to try. See MPEP 2143. In this case, the combination of applied references teaches a finite number of substitutions that can be made in antibody Fc domains in order to improve functions. The art also provides experimental testing of the substitutions allowing for predictable modifications of the Fc domains. Therefore, one of ordinary skill in the art would have been able to pursue the known, potential solutions with a reasonable expectation of success.
Furthermore, it would have been obvious to an ordinarily skilled artisan to use the human IgG Fc domain and the substitutions disclosed in the prior art as a starting point for optimization that was routine in the art in order to achieve the desired Fc properties. See MPEP 2144.05 (II) A. In this case, the combination of applied references demonstrate that modification to Fc domains were routine in the art as were optimizing properties of the modified Fc domains using amino acid substitutions. Therefore, it would have been obvious to use the substitutions taught in the prior art as a starting point to determine the optimal Fc sequence for a given polypeptide application.
Regarding claims 21 and 23 the recited limitations are functional properties that are inherent to the amino acid sequence of the mutant Fc domain. As discussed above, the combination of US’284, US’371, US’283, and US’178 teach a parent domain and substitutions rendering instant SEQ ID NO: 2, or variant V8.2, obvious. The functional properties recited in claims 21 and 23 are inherent to this amino acid sequence, as evidenced by the instant disclosure, Table 5, and; therefore, would flow naturally from following the suggestions of the prior art. See MPEP 2145 II.
Claims 15 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 as applied to claims 1 and 12-13 above, and in further view of US 2010/0184959 A1 (Guler-Gane G., et al) 22 Jul 2010.
US’284 teaches the polypeptide of claim 1 as discussed in detail above.
US’284, however, does not disclose that the Fc domain further comprises a substitution mutation of R292Q.
US’959 teaches methods for selecting, obtaining, or producing Fc variant polypeptides which show altered recognition for an Fc ligand, e.g., FcγR, CIq. Additionally, the Fc variant may have altered ADCC and/or CDC activity. US’959 further teaches methods and protocols for the application of the Fc variants, particularly for therapeutic purposes (abstract).
US’959 teaches methods in which a wild-type Fc polypeptide comprises one or more substitutions including 292Q, which is R292Q, and teaches this substitution in Fc polypeptides that are capable of binding to FcγRIIb (page 4, [0047]-[0049]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polypeptide of US’284 to further include a R292Q substitution as disclosed by US’959. It would have been obvious to further include the R292Q mutation as US’959 teaches the substitution as an additional substitution that can be made in wild-type Fc polypeptides in order to alter effector activity by altering Fc ligand recognition for therapeutic purposes. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’284 and US’959 both teach Fc modification as a means to optimize Fc containing therapeutics, demonstrating analogous art.
Claims 16 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 in view of US 2010/0184959 A1 (Guler-Gane G., et al) 22 Jul 2010 as applied to claims 15 and 17 above, and in further view of US 2016/0376371 A1 (Ravetch, J., et al) 29 Dec 2016.
The combination of US’284 and US’959 teach the polypeptides of claims 15 and 17 as discussed in detail above.
As discussed above, US’284 teaches the parent human IgG Fc domain SEQ ID NO: 1. US’284, SEQ ID NO: 1 has the following alignment with instant SEQ ID NOs: 4 and 5, respectively:
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As discussed above, US’284 also teaches modifications that can be made in the Fc domain including E233V, L234D, L235F, G236R, G237D, S239L, S267D, H268P, T299A, A327L, L328A, A330H, and E333I. As discussed above, US’959 teaches a substitution of R292Q.
The combination of US’284 and US’959, however, do not disclose the mutation of S298G, which is also present in the instant sequences.
The teachings of US’371 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polypeptide taught by the combination of US’284 and US’959 to further include a S298G mutation as taught by US’371. An ordinarily skilled artisan would have been motivated to further include the S298G mutation as US’371 teaches that such mutation, in combination with T299A, can restore effector function, increase signal strength, and the activation of cells. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches the mutation T299A, which US’371 teaches in combination with the S298G mutation.
The conclusion of prima facie obviousness is further supported by KSR(E) obvious to try. See MPEP 2143. In this case, the combination of applied references teaches a finite number of substitutions that can be made in antibody Fc domains in order to improve functions. The art also provides experimental testing of the substitutions allowing for predictable modifications of the Fc domains. Therefore, one of ordinary skill in the art would have been able to pursue the known, potential solutions with a reasonable expectation of success.
Furthermore, it would have been obvious to an ordinarily skilled artisan to use the human IgG Fc domain and the substitutions disclosed in the prior art as a starting point for optimization that was routine in the art in order to achieve the desired Fc properties. See MPEP 2144.05 (II) A. In this case, the combination of applied references demonstrate that modification to Fc domains were routine in the art as were optimizing properties of the modified Fc domains using amino acid substitutions. Therefore, it would have been obvious to use the substitutions taught in the prior art as a starting point to determine the optimal Fc sequence for a given polypeptide application.
Regarding claims 21-24 and 53-55, the recited limitations are functional properties that are inherent to the amino acid sequence of the mutant Fc domain. As discussed above, the combination of US’284, US’959, and US’371 teach a parent domain and substitutions rendering instant SEQ ID NOs: 4 and 5, or variants 2b18KQ and 2b18KQS, obvious. The functional properties recited in claims 21-24 are inherent to these amino acid sequences, as evidenced by the instant disclosure, Table 5 and [00222], and; therefore, would flow naturally from following the suggestions of the prior art. See MPEP 2145 II.
Claims 32-44 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 as applied to claim 1 above, and in further view of US 2004/0175786 A1 (Choi, I) 09 Sept 2004.
US’284 teaches the polypeptide of claim 1 as discussed in detail above.
As discussed above, US’284 teaches aglycosylated and glycosylated Fc domains, a T299A modification, and teaches that the Fc mutant human IgG Fc domains can be comprised in a multimeric oligomer. US’284 further demonstrates that position 309 in IgG1 Fc (SEQ ID NO: 1) is leucine (Leu, L), that position 298 is serine (ser, S), and that position 299 is threonine (Thr, T) (Fig. 3b-1 – 3b-2).7
US’284, however, does not disclose that the multimeric oligomer is a hexameric Fc fusion protein.
US’786 teaches the use of single chain antibodies in polymeric form, e.g., as a dimer, a tetramer, pentamer, hexamer, or a mixture thereof. These forms distinguish themselves over the monomeric ones by an increased avidity (page 2, [0011]). US’786 further teaches the incorporation of IgM tailpieces and the use of such tailpieces for polymerization of the antibody. It is demonstrated that the tailpiece influences polymerization pattern and antibody production while not substantially influencing binding specificity (page 1, [0005]).
Figure 2 of US’786 provides a schematic in which the tailpiece is shown as an addition to the end of the antibody Fc region (Fig. 2a) as well as tailpiece sequences that were tested (Fig. 2b) including IgA wt, three IgM variants, C575S, and VAEVD (page 3, [0023]-[0027]).
US’786, SEQ ID NO: 1, is the same as instant SEQ ID NO: 6, as shown in the ABSS alignment below:
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US’786 further demonstrates the formation of hexamers using the sequence (Fig. 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polypeptide of US’284 to comprise the mutant human IgG Fc domain in a multimeric oligomer, including a hexamer fusion protein using the tailpiece of US’786, SEQ ID NO: 1 as disclosed by US’786. An ordinarily skilled artisan would have been motivated to form a multimeric oligomer, such as a hexamer, in order to increase antibody avidity as disclosed by US’786. The modification is further motivated by US’284, which teaches that multimeric Fc polypeptides provide multiple binding sites for Fc receptors with a single protein molecule. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches that the mutant human IgG Fc domains can be included in multimeric oligomers and US’786 teaches methods of making hexameric multimeric antibody oligomers, demonstrating analogous art.
Claims 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0315284 A1 (Lazar, G.A., et al) 05 Nov 2015 in view of US 2004/0175786 A1 (Choi, I) 09 Sept 2004 as applied to claim 37 above, and in further view of US 2010/0184959 A1 (Guler-Gane G., et al) 22 Jul 2010, US 2016/0376371 A1 (Ravetch, J., et al) 29 Dec 2016, and Rowley, T.F., et al (2018) Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune complex interactions Communications Biology 1(146); 1-12.
The combination of US’284 and US’786 teach the polypeptide of claim 37 as discussed in detail above.
The combination of applied references, however, does not disclose that the hexameric Fc fusion protein comprises one of the recited SEQ ID NOs.
The teachings of US’959 and US’371 are as discussed above.
As discussed in detail above in the rejection of instant claim 18, the combination of US’284, US’959, and US’371 render obvious a polypeptide of instant SEQ ID NO: 5 and US’786 teaches the addition of a tailpiece of US’786, SEQ ID NO: 1 to the end of the Fc domain as a means to create a hexamer.
The combined teachings of US’284, US’786, US’959, and US’371 teach a sequence that is identical to instant SEQ ID NO: 7 with the exception of a single mutation in Kabat position 309 of L309C.
Rowley teaches the construction of Fc hexamers and, in Fig. 1, page 2, provides a schematic of the structure of Fc hexamers. Rowley teaches that Fc hexamers consist of the human IgG Fc hinge-CH2-CH3 domains fused to an IgM tailpiece domain, which provides stable hexamerization. In the schematic a L309C mutation is included which generates an additional cysteine bond. Rowley further teaches that the hexamers are generated by fusion of the human IgM tailpiece at the C terminal. Rowley teaches that the tailpiece has a sequence of PTLYNVSLVMSDTAGTCY (page 2, right column, paragraph 2), which is identical to the tailpiece taught by US’786.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the polypeptide disclosed by the combination of US’284 and US’786 to further include a R292Q substitution as disclosed by US’959, a S298G substitution as taught by US’371, and a L309C substitution as taught by Rowley. It would have been obvious to further include the R292Q mutation as US’959 teaches the substitution as an additional substitution that can be made in wild-type Fc polypeptides in order to alter effector activity by altering Fc ligand recognition for therapeutic purposes. An ordinarily skilled artisan would have had a reasonable expectation of success as both US’284 and US’959 both teach methods of optimizing Fc domains for therapeutic purposes. An ordinarily skilled artisan would have been motivated to further include the S298G mutation as US’371 teaches that such mutation, in combination with T299A, can restore effector function, increase signal strength, and the activation of cells. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches the mutation T299A, which US’371 teaches in combination with the S298G mutation. It would have been obvious to introduce a L309C mutation as Rowley teaches this mutation in hexamers in addition to the IgM tailpiece as a means to form a disulfide bond. An ordinarily skilled artisan would have had a reasonable expectation of success as US’284 teaches that the mutant human IgG Fc domains can be included in multimeric oligomers and US’786 and Rowley teach methods of making hexameric multimeric antibody oligomers, demonstrating analogous art.
Response to Arguments
Applicant’s arguments concerning the rejections under 35 USC 103 above in the response filed 07/29/2026 have been fully considered but are not persuasive.
Applicant argues that US’284 generally relates to the generation of Fc variants and recites the wild type IgG sequence, but does not provide the combination of Fc mutants instantly claimed. Applicant argues that US’284 teaches 117 positions with a possibility of 20 amino acid possibilities that could be substituted into the position which is more than 3.094*1014 possible Fc mutations. Applicant argues that these possibilities do not represent a “finite number” of identified and predictable solutions. Applicant cites MPEP 2143 as siting that there must be a finite number of identified and predictable solutions to provide a prima facie case of obviousness. Applicant argues that the huge number of possible Fc mutants that could be generated, based only on introducing substitution mutation(s) within the region disclosed by US’284, does not represent “predictable” solutions. Applicant further argues that the action does not establish that combinations of substitution mutations- further ones that were not previously generated or tested- would yield predictable results.
Applicant further argues that US’284 does not teach the instantly claimed combinations and that the vast majority of mutations in US’284 are irrelevant to the mutations recited in the pending claims. Applicant argues that, therefore, the art does not provide all elements of the instant claims.
These arguments are not persuasive.
US’284 teaches specific positions for mutation and the specific mutations disclosed are within the range 221-337, however, US’284 does not teach or suggest that every position in the range 221-337 is mutated as suggested by applicant in the response. Rather, as discussed in the rejection, US’284 teaches 88 specific positions within the range for substituting. Additionally, as discussed in the rejection, US’284 does not suggest that the positions could be substituted with any of the known 20 amino acids, but, rather, provides preferred substitutions that provide specific amino acid substitutions (page 4, [0020]). US’284 also teaches that the Fc variants can have combinations of the substitutions disclosed (page 5, [0021]).
The rejection is based on these specific teachings of US’284, not the full span of 117 positions between amino acids 221 and 337 with any of the 20 known amino acids as suggested by applicant.
MPEP 2143, as cited by applicant, states that “[t]he KSR Court recognized that "[w]hen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp." KSR, 550 U.S. at 421, 82 USPQ2d at 1397.” The MPEP section further states that “ the Supreme Court’s requirement in KSR for "a finite number" of predictable solutions when an obvious to try rationale is applied: under the Federal Circuit’s case law "finite" means "small or easily traversed" in the context of the art in question.”
In this case, as discussed above, US’284 teaches a finite number of specific positions as well as mutations that can be made in the human IgG Fc region to optimize binding. While applicant may calculate an expanded number to say that the combinations that could be made are numerous, the teachings of US’284 demonstrates that the finite number of substitutions presented would be easily traversed in the context of the art in question.
Furthermore, while applicant argues that the results would not be predictable, US’284 constructed variants with individual substitutions and provides testing data for the variants which would be expected to allow for predictable modification.
With regards to applicant’s arguments that combinations of substitutions, specifically ones that were not generated or tested, would not yield predictable results, it is considered that conclusive proof of efficacy is not required in order to establish a prima facie case of obviousness. Rather, the standard for obviousness is a reasonable expectation of success.
MPEP 2143.02 (I) states that “conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”.
As such, none of the applied prior art, including US’284, is required to experimentally demonstrate the claimed combination in order to establish obviousness.
Furthermore, while applicant argues that US’284 teaches mutations that are irrelevant to the instantly claimed combinations, the independent claim uses “comprising” language with regards to the substitution mutations that are present in the human IgG Fc domain. In the absence of a limiting definition for “comprising”, the transitional phrase is interpreted according to MPEP 2111.03 I, which defines “comprising” as being “synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.”
As such, claims which use the transitional phrase “comprising” encompass embodiments in which additional, unrecited, substitutions can be made in addition to those recited in the claims, for instance, those taught by US’284.
Applicant further argues that the data provided in the examples and figures of the instant application showing altered FcR binding of the mutant Fc as instantly claimed, such as increased binding to FcγRIIB with decreased or eliminated binding to activating FcR and C1q constitutes “surprising and unexpected” results that should be considered as secondary considerations of nonobvious, citing MPEP 2145 for support.
The examples of the disclosure detail a library construction strategy for the isolation of IgG1 Fc domains that bind to FcγRIIB (page 75, Example 1). A list of Fc variants that were identified and used in further experiments is shown in Table 4 (pages 76-77), which is duplicated below for convenience.
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The disclosure identifies EF, V12, and V11 as Fc variants that were already known in the prior art while V8.2, 2b18K, 2b18KQ, and 2b18KQS are the Fc variants of the instant invention (page 76, [00210]). It is also noted that the disclosure identifies V8.2 as instant SEQ ID NO: 2; 2b18K as SEQ ID NO: 3; 2b18KQ as SEQ ID NO: 4; and 2b18KQS as SEQ ID NO: 5. These sequences represent the species of the claimed invention that applicant demonstrates in the examples provided.
The examples disclose that, to verify the binding affinity to Fcγ receptors, biolayer interferometry assays were performed. Results are shown in Table 5 (pages 78-79), which is duplicated below for convenience.
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The example teaches that FcγRIIb-selective Fc variant candidates, 2b18K, 2b18KQ, and 2b18KQS, showed FcγRIIb binding with no or very low binding affinity to activating receptors (page 80, [00212]). To measure the binding affinity of 2b18KQS Fc variant more accurately, SPR was performed with 2b18KQS variant and results are provided in table 6, which is duplicated below for convenience (pages 80-81, [00213]).
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Table 6 demonstrates reduced C1q binding only for the 2b18KQS Fc variant. The example also only compares the result with the wild type Fc domain.
In the response, applicant does not specifically identify any particular result that is alleged to be unexpected/surprising and the only reference to any specific result is increased binding to FcγRIIB with decreased or eliminated binding to activating FcR and C1q.
While applicant does compare the tested Fc variants and Fc receptor binding to EF, V12, and V11 which are disclosed as Fc variants that were already known in the prior art, the examples do not provide C1q binding data for any variant other than 2b18KQS, and only compares the results to the wild type Fc domain to demonstrate a reduction in binding. Additionally, the art recognizes the EF and V12 variants as having high or enhanced affinity for FcγRIIb, but also as maintaining binding affinity for the Fc activating receptors and the comparison results to these Fc variants is not surprising. With regards to V11, the art recognizes the variant as having selective and strongly enhanced binding affinity for the inhibitory FcγRIIb receptor and a reduction in affinity for the activating receptors. Affinity differences which appear to be demonstrated in applicant’s comparison in measurements which were assayed. For instance, the variant shows reduced affinity to FcγRIIaH131, FcγRIIaR131, and FcγRIIIaV158, and significantly higher FcγIIb binding. It is not apparent from the example that the instantly tested variants are unexpected compared to V11, which could be considered to be the closest prior art that was tested by applicant. This is particularly the case in view of the teachings of US’284, which teaches modifications that can be made to optimize Fc binding and also teaches that the Fc variants may have enhanced affinity for FcyRIIb, yet reduced affinity to one or more activating FcRs. It is also noted that the closest prior art would be considered to be the mutations taught by US’284, a comparison of which is not provided by applicant.
Additionally, it is noted that MPEP 716.02 states “A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent.”
Furthermore, if it were found that the results provided are unexpected, which it is not, the results provided for the specifically identified outcomes are not commensurate in scope with the claims.
MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
Independent claim 1 is drawn to a mutant or variant human IgG Fc comprising the substitutions E223V, S239L, H268P, A327L, L328A, and substitutions in positions 234 and 235, which are not limited to any specific amino acid.
The claim is drawn to a genus of mutants/variants in which the recited substitutions are made and, as discussed above, can also include additional unrecited substitutions. Applicant, however, does not demonstrate that the results would be maintained over the entire scope of the claim.
The only species of the claim tested by applicant are V8.2, 2b18K, 2b18KQ, and 2b18KQ, and the specification identifies only variant candidates, 2b18K, 2b18KQ, and 2b18KQS, showed FcγRIIb binding with no or very low binding affinity to activating receptors. The only results identified in the specification regarding C1q binding is for the Fc region 2b18KQS, which is instant SEQ ID NO: 5.
As such, it is not clear that the results provided in the specification would span the entire scope of the claim and, therefore, the claims are not commensurate in scope with the claimed invention.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
