DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s election without traverse of Group I (drawn to a polypeptide) and the species of 329G and 238P in the reply filed on July 17, 2026 is acknowledged.
Claims 1-19 are pending.
Claims 18 and 19 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected invention.
Applicant was notified regarding improper multiple dependent claims and use claims in the Office Action mailed on April 20, 2026. These claims remained unamended in applicant’s response. Specifically, the Office Action mailed on April 20, 2026 states:
Claims 4-14 are in improper form because a multiple dependent claim cannot be depended from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, claims 4-14 have not been further treated on the merits.
Further, it is noted that claims 15-17are directed to the “use” of a polypeptide”. "Use" claims are non-statutory under 35 U.S.C. 101 because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki , 153 USPQ 678 (Bd. App. 1967) and Clinical Products, Ltd v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966). See MPEP 2173.05(q).
Therefore, claims 15-17 have been withdrawn from consideration as being drawn to non-statutory subject matter.
Consequently, claims 4-19 have been withdrawn.
Claims 1-3 are currently under consideration as they read on the elected invention.
3. 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.
4. Claims 1-3 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-3 are drawn to a polypeptide comprising an Fc variant of a wild-type human IgG Fc region, said Fc variant comprises an amino acid substitution at position P329 and at least one further amino acid substitution, wherein said polypeptide exhibits a reduced affinity to huma FcγRIIIa, and/or FcγRIIA and/or FcγRI, and a reduced ADCC of at least 20% relative to a polypeptide comprising a wild-type human IgG Fc region. Dependent claim 2 further recited that eh P329 substitution is P329G or P329R, or P329 substituted with an amino acid residue large enough to destroy the proline sandwich within the Fc/Fcγ receptor interface.
Claim 1 provides no indication of the amino acid residues that can be introduced in place of the proline at position 329 and also does not recite what or where the additional substitutions may be. Claim 2 recites P329G or P329R, or any amino acid residue defined by function (large enough to destroy the proline sandwich within the Fc/Fcγ receptor interface) rather than structure of the amino acid residues that can be used to replace proline in position 329.
The specification discloses Fc variants P329G, P329A, P329R, S228P/L235E (“SPLE”), L234A/L235A (“LALA”), P329G/LALA, and P329GSPL, e.g. see Example 1 in page 79 of the specification as-filed. The specification further discloses IgG1 anti-CD9 antibodies containing L234A, L235A, P329G, P329G/LALA and IgG4 anti-CD9 antibodies containing P329G, S228P/L235E, and P329G/SPLE mutations. The specification shows that combining the P329G mutation with the SPLE or LALA mutations resulted in a greater reduction in binding to FcγRI. (see page 82, and Fig. 1a, b). P329G also strongly reduced binding to FcγRIIA, as did the LALA, and P329G/SPLE, P329G/LALA combinations. (see page 83 and Fig. 1c.) Reduced binding to FcγRIIIA required the triple mutations P329G/LALAL or P329G/SPLE, or the P329G mutation, as the LALA and SPLE mutations had little effect. (see page 83 and Fig. 1e.) Reduced C1q binding is shown for the P329G and SPLE mutations. (see page 84 and Fig. 2.) Reduced ADCC is reduced by P329G, P329R, LALA, and P329G/LALAL. (Pages 84, 87, Fig. 3 and Fig. 4.) A P329A variant had less effect. CDC activity was inhibited by P329G and P329G/LALAL. (see page 88, Fig. 5). Regarding S228P substitution, the specification discloses that it would be made in only in human IgG4 (e.g. see lines 25-33 in page 1 of the specification as-filed).
The specification discloses that in vitro assays showing that IgG1 antibody (e.g. anti-CD9 antibody) comprising amino acid substitutions in the Fc region such as P329G or P329A without or without other specific substitutions (e.g. L234A and L235A) exhibits decreased binding affinity to Fcγ receptors such as FcγRIIIA receptor and reduced ADCC function (e.g. see Examples in pages 79-90).
However, there is insufficient written description in the specification as-filed of the claimed polypeptide comprising an Fc variant comprising an amino acid substitution at position P329 and at least one further amino acid substitutions, wherein said polypeptide exhibits a reduced affinity to one or more human FcγRIIIA, FcγRIIA, and FcγRI compared to the polypeptide comprising the wildtype IgG Fc region, and wherein the ADCC induced by the polypeptide is 1-20% of that induced by the polypeptide comprising a wild type Fc.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See MPEP 2163 II.A.3a.ii.
The claims recite a genus of a polypeptide comprising the Fc variant wherein the polypeptide also exhibits effector functions such as ADCC which is mediated by antibody. The specification does not describe the structure for binding protein other than IgG antibody comprising structurally defined Fc variants. The specification does not describe the particular physical or chemical characteristics for the polypeptide nor does the specification disclose sufficient correlations between the structure of polypeptide and the function of reducing effector functions (e.g. ADCC).
For example, Teillaud (July 2012, ADCC. In:eLS. John Wiley & Sons, Ltd: Chichester. Pages 1-8, reference on IDS) teach that ADCC is triggered through interaction of target-bound antibodies (belonging to IgG or IgA, or IgE classes) with certain Fc receptors present on effector cell surface (e.g. see Abstract and Figure 2 in page 3).
Shield et al. (JBC 2001, 276;9:6591-6604, reference on IDS) teach that that while a common set of IgG1 residues is involved in binding to all Fc[Symbol font/0x67]Rs; Fc[Symbol font/0x67]RIII also utilize residues outside the common set (e.g. see particularly page 6591).
The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between functions of reduced effector functions including ADCC and structure of the polypeptide comprising an Fc variant comprising amino acid substitution at position P329 and at least one further amino acid substitution, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of the polypeptide broadly encompassed by the claimed invention.
It does not appear based upon the limited disclosure of the IgG antibodies comprising specific amino acid substitutions (e.g. P329G or P329 in combination of S228P in human IgG4 Fc region) alone that Applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the limited number of species disclosed and the extensive variation permitted within the genus of the polypeptide.
“Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997).
The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406.
In the absence of disclosure of relevant, identifying characteristics of the polypeptide, there is insufficient written disclosure under 35 U.S.C. 112, first paragraph.
Therefore, there is insufficient written description for genera of polypeptide, broadly encompassed by the claimed invention, other than the antibodies comprising structurally defined Fc variants, in the specification as filed under the written description provision of 35 USC 112, first paragraph.
5. 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.
6. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
7. Claims 1-3 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Graus et al. (7,563,441, Gaus, reference on IDS) in view of Presta (US 6,737,056, reference on IDS).
Graus teaches an anti-P-selecting antibody comprising reduced binding to C1q and reduced binding to Fcγ receptors (e.g. see Abstract). Graus teaches “[t]he antibodies according to the present invention antibodies preferably do not elicit any effector function and do not bind to Fc.gamma.R presented on NK cells” [e.g. see (44)]. Graus teach that it was known amino acid alteration in positions Pro329, 234, and 235 can produce an Fc variant with reduced FcγR binding; and states that “Especially preferred are the mutations S228P (IgG4), L234A (IgG1), L235A (IgG1), L235E (IgG4), GLPSS331(IgG1) and/or PVA236 (IgG1)” [e.g. see (45)].
Graus teaches construction of expression plasmids for mutant variant IgG1 and IgG4 with IgG1 antibody with mutations L234A and L235A (IgG1v2) in the Fc region and IgG4 with S228P and L235E in the Fc region (IgG4v1) (e.g. see Col. 32 and Table 1). Graus teaches that the IgG1v2 and IgG4v1 both show reduced C1q binding compared to unmodified antibody (e.g. see Table 3 in Col. 40) and reduced binding to Fcγ receptors including FcγRIIIA, FcγRIIA.
The teachings of the reference differ from the instant invention by not describing an additional Pro329G substitution.
However, P329G substitution in the Fc region of an antibody or Fc fusion protein for reducing effector functions were well-known in the art at the time the invention was filed. For example, Grous teaches substitution in Pro329 for an Fc variant with reduced effector function (see discussion above). Presta teaches examples of IgG1 antibody Fc variant mutated in the Fc region with P329A and shows that the Fc variant exhibits reduced binding to FcγRI, FcγRIIA, and FcγRIIIA (e.g. see Table 6 in col. 57-58). Presta also teaches the Pro329 mutation reduced C1q binding which correlates with reduced CDC activity (e.g. see col. 24, lines 32-40). In addition, Presta teaches mutating P329 along with one or more other mutations to reduce CDC and FcγR binding at multiple locations (e.g. see col. 5 lines 1-30,; col. 22, line 55 to col. 23, line 9; col. 24, lines 52-56; and Table 6).
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to add P329G substitution disclosed by Presta to the IgG1 Fc region with L234A and L235A mutations in Graus for an Fc variant with reduced binding to FcγRs and C1q and reduced effector functions (e.g. reduced ADCC, CDC). This is because Graus shows that those particular mutations in the Fc region are effective in blocking C1q-based CDC and FcγR based ADCC. Therefore, the ordinary artisan would have had motivation to select the particular combination of mutations for inclusion along with Presta’s P329 mutations (e.g. P329A or P329G) as the additional mutation and a reasonable expectation that these combinations L234A/L235A/P329G, or P329G/S228P in human IgG4 would have been more effective in reducing or abolishing the effector function including ADCC and CDC. Note that P329 is conserved in the Fc region of both human IgG1 and human IgG4 (e.g. see FIG.23 in Presta).
The P329G with L234A and L235A or P329G with S228P in the Fc region of human IgG1 and IgG4, respectively, would necessarily reduce the binding of the Fc to FcγRI, FcγRIIIA, and FcγRIIIA, and it would also necessarily reduce ADCC “0-20%” as compared to unmodified wild type antibody, since it is substituted at the same residues at the same positions as claimed. As such, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
8. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
9. Claims 1-3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. 8,969,526 (the ‘526 Patent, reference on IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the claims in the ‘526 Patent are drawn to the same or nearly the same isolated polypeptide comprising an Fc variant of human IgG1 or human IgG4 comprising amino acid substitutions P329G or P329R, and additional substitutions including L234A and L235A in human IgG1 Fc region or additional substitution S228P in human IgG4 Fc region. The species of the human IgG1 and IgG4 Fc region with specific amino acid substitutions P329G or P329R with additional specific substitutions L234A and L235A or S228P recited in the ‘526 Patent would anticipate the instant claims encompassing an amino acid substitution at position P329 and at least one further amino acid substitution.
10. No claim is allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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