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
Claims 18-19 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. The
Elected Subspecies A2 (a single and specific structural arrangement selected from (a)-(e) of claim 10 and a single and specific species of variable domain) has been determined as free of the prior art according to the present record. Pursuant to the procedures set forth in MPEP § 803.02 III. C. 2., all nonelected species of Subspecies A2 a single and specific structural arrangement comprising antigen binding domains, previously withdrawn from consideration as a result of the restriction requirement mailed September 17, 2024, are hereby rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement with respect to Species A, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Restriction stands with respect to Subspecies A1, which has been expanded to encompass IgG1 and IgG4. IgG2 and IgG3 remain withdrawn from consideration. Restriction stands with respect to Subspecies A3 to a single and specific TD domain of p53.
Status of Claims
Claims 1, 4-5, 7-13, and 16-22 are currently pending. Claims 1, 4-5, 7-13, 16-17, and 20-22 are under examination as claims 18-19 stand withdrawn pursuant to 37 CFR 1.142(b).
WITHDRAWN OBJECTIONS and/or REJECTIONS
Applicant’s amendments and/or arguments, filed May 8, 2025, with respect to:
Objection to the sequence listing, specification, drawings and claim 13 (see Remarks on pg. 10 in the last ¶ through pg. 11 in the fourth ¶);
Rejection of claims 1-3, 7-10, 12-13, and 16-17 under 35 U.S.C. § 101 (see Remarks on pg. 15 in the last ¶ through pg. 17 in the second ¶);
Rejection of claims 1-3, 7-10, 12-13, and 16-17 under 35 U.S.C. § 102 (see Remarks on pg. 17 in penultimate ¶ through the first full ¶ on pg. 20);
Rejection of claims 1, 4-5, 7-13,16-17, and 20-22 under 35 U.S.C. § 103 over Willuda in view of Wu or Parren (Remarks pg. 20 in the penultimate ¶ through pg. 22; Particularly, Applicant points out it would be nonobvious to multimerize half-Ig when the rationale for obtaining a half-Ig, as taught by Wu or Parren, is greater tissue penetration from decreasing the size of a natural antibody); and
Double patenting rejections over U.S. Pat. No. 11,453,726 in view of Wu or Parren; or App. No. 17/817,912 in view of Wu or Parren (see Remarks pg. 23-27)
have been fully considered and are persuasive. The aforementioned grounds of objection and/or rejection has been withdrawn.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112
Claims 1, 4-5, 7-13, 16-17 and 20-22 stand 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.
Applicant's arguments filed May 28, 2025 have been fully considered but they are not persuasive.
Applicant alleges that the rejection, with respect to the term “Fc” is overcome by amending claim 1 to recite “[a] protein multimer comprising a plurality of polypeptides, each polypeptide comprising (a) an antibody Fc region, wherein the Fc region comprises an IgG CH2 domain and an IgG CH3 domain; and (b) a self-associating multimerization domain (SAM); wherein each Fc is devoid of a core hinge region comprising amino acid sequence CXXC, wherein X is any amino acid.” (pg. 12 in the first full ¶).
However, this argument is unpersuasive because the amendment does not clarify whether “a polypeptide comprising… an antibody Fc region” encompasses, e.g. a single chain Fc comprising dimerized CH2 and CH3 domains, a single polypeptide comprising CH2-CH3 which may or may not be dimerized with another CH2-CH3 polypeptide, or whether the claim, as Applicant alleges, would unambiguously be interpreted by the skilled artisan as being limited to an Fc monomer comprising CH2-CH3 that has been altered / modified / mutated to prevent homodimerization.
Applicant states that “a key aspect of the present invention is that the recited Fc does not directly pair with another Fc, which aids in formation of the claimed protein multimer through the SAM domain.” However, the structural elements recited in claim 1 do not preclude the formation of dimerized Fc under physiological conditions because individual heavy chains are known to dimerize via non-covalent CH3 to CH3 interactions, even in the absence of disulfide bonds provided by the CXXC hinge motif. Examiner maintains that the person of ordinary skill in the art would interpret “Fc” (aka fragment crystallizable), according the plain and ordinary meaning, as the fragment from a full antibody that is obtained via, e.g., papain digestion and comprises two dimerized polypeptides comprising CH2-CH3. Examiner also maintains the position that the instant specification neither clearly redefines the term “Fc” or disavows the scope of the plain and ordinary meaning. See MPEP 2111. Applicant has not pointed out where the plain and ordinary meaning of the term “Fc” is clearly and unambiguously redefined or disavowed, therefore the arguments are not found unpersuasive.
With respect to the arguments regarding “CH2” Examiner notes that the term “CH2” has been removed from the claims thus obviating the rejection with respect to this aspect.
With respect to the scope of “epitope binding site,” (see arguments on pg. 15 in the first full ¶ through the penultimate ¶), has been clarified by the amendments because the scope of “a protein multimer” comprising an “epitope binding site” clearly encompasses the scope of binding domains that require more than one polypeptide – i.e. VH/VL – as well as single polypeptide binding domain such as sdAb and scFvs.
Regarding instant claim 7, claim 1 has been amended to remove “wherein the CH2 comprises an antibody hinge sequence,” however claim 7 references “the hinge sequence” in line 3. The term “the hinge sequence” lacks antecedent basis because claim 1 does not specify that the Fc region comprises a hinge sequence. Rather, claim 1 recites “the Fc region is devoid of a core hinge region.” Thus, the skilled artisan would interpret claim 1 as encompassing both Fc regions comprising an upper hinge region, CH2, and CH3 and Fc regions completely lacking hinge. The metes and bounds of claim 7 are thus unclear because the skilled artisan would not be able to determine whether claim 7 further limits the Fc region to an Fc region comprising a hinge that is devoid of the core hinge region (i.e. upper hinge-CH2-CH3). In other interpretations, claim 7 encompasses the scope of Fc regions completely lacking an upper and core hinge sequence, wherein “the hinge sequence” references the lower hinge region, which is also component of CH2.
Claims 4-5, 8-13, 16-17 and 20-22 stand rejected by virtue of their dependency. For the purpose of applying art, the claims are interpreted as encompassing a multimer of paired heavy chain or single chain Fc, wherein the Fc comprises a SAM and lacks a core CXXC hinge sequence. Regarding claim 7, “the hinge sequence” is interpreted as an optional limitation, thus a teaching of an Fc comprising from N- to C-terminal a CH2 domain and a CH3 domain teaches the limitations of the Fc region according to the claim.
Claim Rejections - 35 USC § 102
Claims 1, 4-5, 7, 16-17, and 20-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Block in US 2013/0156765 A1 published June 20, 2013.
Applicants amendments necessitate new grounds of rejection.
Previously, claim 1 was generic regarding the species of Fc region, and was anticipated by art teaching IgA and IgM constant regions (see Office Action mailed 2/26/2025 on pgs. 23, last ¶ through pg. 25). Amendments limiting the scope of Fc regions to IgG regions overcame the previously applied 102 rejections. Applicants also incorporated an element of claim 15 by amending claim 1 to recite “protein multimers comprising.” However, claim 15 was limited to unpaired Fc, which is narrower in scope than the protein multimer of instant claim 1 (see rejection under 35 U.S.C. 112(b) above). Thus, the amendments to recite a combination of limitations directed to a protein multimer and IgG Fc has not previously been considered with the instantly claimed scope which encompasses a protein multimer of paired IgG Fc polypeptides comprising a SAM.
In ¶ [0032] on pg. 4, Block teaches a stradomer comprising a leader sequence directly linked to a multimerization domain directly linked to an IgG1 Fc domain which consists of IgG1 CH2 and CH3, wherein the multimerization domain creates multimers of the stradomer units. “Consists of” is interpreted as a closed group that excludes other components. An IgG1 Fc domain consisting of IgG1 CH2 and CH3 is interpreted as excluding upper and core hinge and is, thus, inherently devoid of a core CXXC sequence and upper hinge EPKSCDKTHT (SEQ ID NO: 183). A “stradomer” is defined on pg. 9 in ¶ [0076] as “a single, contiguous peptide molecule that, when associated with at least a second stradomer monomer, forms a polypeptide comprising at least two Fc domains[,]” which, as would be interpreted by one of skill in the art, teaches the limitation directed to a polypeptide comprising a hingeless IgG1 Fc and a SAM, wherein the disclosed stradomer multimers are, though not ipsis verbis, protein multimers. Moreover, while Block does not explicitly state that the multimerization domain is a “self-associating” multimerization domain, Block does expressly teach that the multimerization domain creates multimers of the stradomer, thus the stradomers can be said to “self-associate” via the multimerization domain. Therefore, there is no structural or functional difference between the multimerization domains of Block and the instantly claimed SAM. Thus, Block at ¶ [0032] anticipates instant claim 1, 5, and 21.
In ¶ [81] on pg. 11, Block discloses that the CH2 and CH3 domains of IgG1 are regarded as SEQ ID NO: 19, see also pg. 43 bridging pg. 44. Thus, one of skill reading the reference would have at once envisaged the Fc region at ¶ [0032] as comprising APELLGGPSV (SEQ ID NO: 163) because SEQ ID NO: 19 is the only sequence taught by Block for an IgG1 Fc consisting of CH2 and CH3, anticipating instant claim 4. Additionally and/or alternatively, APELLGGPSV is inherent to an IgG1 CH2 domain as disclosed at ¶ [0032]. Regarding instant claim 16, Block teaches administering the stradomer, e.g. intravenously or with an additional pharmaceutical composition (see ¶’s [0039-0041] on pg. 5). Regarding instant claims 17 and 20, Block teaches expressing recombinant nucleic acid encoding the stradomer molecules of the present invention in a mammalian cell (see ¶ [079] on pg. 11). Regarding instant claim 7, insofar as a skilled artisan would have interpreted a “leader sequence” as necessarily being the N-terminal component, Block, in claim 160, teaches instant claim 7 because one would interpret the following from N- to C-terminus: a leader sequence linked to the IgG1 Fc, wherein the IgG1 Fc is SEQ ID NO: 19, and IgG1 Fc is directly linked to the multimerization domain. Alternatively, one of ordinary skill in the art reading the reference would have at once envisaged this arrangement (see Block at claim 163).
In conclusion, Block anticipates instant claims 1, 4-5, 7, 16-17, and 20-21.
Claim Rejections - 35 USC § 103
Claims 1, 4-5, 7, 12, 16-17, and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Block in US 2013/0156765 A1 published June 20, 2013 as applied to claims 1, 4-5, 7, 16-17, and 20-21 above, and further in view of Timmer in US 2017/0015753 A1 published January 19, 2017.
See Block as applied to claims 1, 4-5, 7, 16-17, and 20-21 above. Block teaches that suitable peptide multimerization regions include, inter alia, isoleucine zippers (pg. 12, ¶ [0086]).
Block teaches a protein multimer comprising polypeptides comprising an IgG1 Fc region comprising CH2 and CH3 and a self-associating multimerization domain, wherein the Fc region is devoid of a core hinge region; Block does not teach that the multimerization domain is p53.
However, Timmer teaches on pg. 10 in ¶ [0082] that leucine zippers and p53 are suitable multimerization domains for antibody-related moieties.
It would have been prima facie obvious to use p53, taught by Timmer, as a multimerization domain for the stradomers taught by Block. Specifically, the function of p53 as a multimerization domain was known in the art at the time of instant filing, as evidenced by Timmer, and one of ordinary skill in the art could have applied p53 as a multimerization domain for the stradomers taught by Block. The application of p53 as a multimerization domain would have predictability resulted in multimerization of the stradomers via the p53 multimerization domain. Moreover, p53 is taught by Timmer as being substitutable for a leucine zipper which is structurally and functionally similar to the isoleucine zipper taught by Block. Therefore, one of ordinary skill in the art would have recognized that p53 is also a suitable alternative for using an isoleucine zipper as a multimerization domain. In conclusion it would have been prima facie obvious to use p53 as taught by Timmer for the multimerization domain of any stradomer taught by Block, arriving the instant invention of claims 12 and 22 with a reasonable expectation of success.
Conclusion
Claims 8-11 and 13 are being regarded as free of the prior art according to the current record.
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.
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/B.K.S./Examiner, Art Unit 1644
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683