Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group 1 (claims 1-5, 7, 11-15, 17, 19, 34, 36, and 48-51 drawn to compositions comprising CD16+ or NK cells and a polypeptide comprising a ligand binding domain and an igG1 CH2 domain with S239D and I332E mutations with respect to an IgG1 sequence relating to SEQ ID NO: 1) and Species A (a single and specific modified CH2 domain comprising S239D and I332E having the additional mutation S324T) in the reply filed on December 17, 2025 is acknowledged.
In view of Examiner’s search, the elected additional mutation of S324T has been expanded to encompass H268F.
Applicant’s representative was contacted to clarify election of Species B with reply received on December 30, 2025. For the purpose of searching, five ligand binding domains have been provisionally elected: Adalimumab, Dupilumab, Nivolumab, Pembrolizumab, and Trastuzumab. In view of Examiner’s search, the elected species has been expanded to include Ocrelizumab.
Claims 16, 33 and 52-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 4, 2025.
Claim Status
Claim 1-5, 7, 11-17, 19, 33-34, 36, and 48-55 are currently pending. Claims 1-5, 7, 11-15, 17, 19, 34, 36, and 48-51 are under examination and claims 16, 33, and 52-55 are withdrawn as set forth above.
Drawings
The drawings are objected to because the axes of Figure 9A are illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
37 CFR 1.71(a) requires the claims to be written in “full, clear, concise, and exact terms”. Claims 1-3, 7, 19, and 36 are objected to because of the following informalities:
Claim 1 and 19 should end with a period rather than a comma.
Claim 36 should begin with “A pharmaceutical composition” rather than “Pharmaceutical composition”.
Claims 1, 2, 19, and 36 recite “SEQ ID NO. 1” or “SEQ ID NO 1”. To be clear and exact, the claims should have consistent formatting and preferably recite “SEQ ID NO: 1”.
Using the term “FcγRIIIa/CD16a” in claim 3 is also inconsistent with the use of term “FcγRIII (CD16)” in claim 1. While the skilled artisan would understand that CD16 and CD16a the same as FcγRIII and FcγRIIIa, respectively, the syntax should be consistent – e.g. using “FcγRIIIa (CD16a)” in place of “FcγRIIIa/CD16a” would be consistent with the rest of the claimed subject matter.
Claim 7 is objected to because while part (I) appropriately begins with “when…., then” part (II) is not a properly conditional limitation and should recite “when” or “if” before “the modified” in line 13.
Appropriate correction is required.
Specification
37 CFR 1.71(a) requires that the specification is written in “full, clear, concise, and exact terms”. The disclosure is objected to because of the following informalities:
Both “SEQ ID NO.” or “SEQ ID NO ” are used. To be clear and exact, the specification should have consistent formatting and preferably recite “SEQ ID NO:”.
Pg. 25 in line 10 – antibody fragment” is missing the opening quote.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-5, 7, 11-15, 17, 19, 34, 36, and 48-51 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.
Regarding claims 1, 2, 19, and 36, the phrase "represented by" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Some skilled artisan would interpret “represented by” as exemplifying language and argue that the limitations of SEQ ID NO: 1 or a sequence 85% identical thereto are not required limitations of the claim. Other skilled artisans would argue that claims 1, 19, and 36 have the scope of a modified CH2 domain with respect to an IgG1 CH2 sequence comprising SEQ ID NO: 1 or a sequence 85% identical thereto.
For the purpose of applying art, the former interpretation is adopted, i.e. a teaching of an human IgG1 CH2 domain comprising S239D and I332E is interpreted as reading on the claimed modified CH2 in the absence of explicit teachings regarding the limitations of SEQ ID NO: 1.
The scope of claims 5 and 7 are indefinite. In claim 5 (a) the CH2 domain comprises at least one mutation selected from a list of three. Alternatively, in claim 5 (b) the CH2 domain comprises at least one mutation from a subset of those listed in claim 5(a). Claim 7 presents conditional limitations, wherein if the at least one mutation is selected from the list of three, then one of said three is required, i.e. A330L, but if the at least one mutation is selected from the list of two then any combination of the mutations of claim 1 with one or more of the two is possible. Since the list of two is a subset of the list of three, it is unclear under what conditions the structure of claim 7 is further limited to A330L. For example, a CH2 domain comprising an H268F is at least one addition mutation selected from H268F and S324T and it is also at least one addition mutation selected from H268F, S324T, and A330L. Therefore, it is unclear whether, according to claim 7, the structure comprising H268F should further require an A330L mutation.
For the purpose of advancing prosecution any additional single or combination of H268F, S324T, and A330L is interpreted as reading on both claims 5 and 7.
Claim 12 is indefinite because it is unclear how the structure of the CD16+ is further limited. For example, there are no positively recited structural features conferred by the phrase “allogeneic with respect to an individual in need thereof.” Indeed, to have the quality of being “allogeneic” the presence of a second biological structure is required. Some skilled artisan would argue that claim 12 therefore requires the limitation of “an individual” to which the CD16+ cell is allogeneic – i.e. claim 12 is limited a composition comprising said CD16+ cell and an individual to which the CD16+ cell is allogeneic. Applicant is respectfully placed on notification that a rejection under 35 U.S.C. § 101 for claiming a Human Organisms may be appropriate if the intended scope of claim 12 requires the structure of “an individual in need thereof “ to which the CD16+ cell is allogeneic. Other skilled artisans would argue that the structure of said individual is not a required limitation of the claim and there is not further limitation of the CD16+ cell defined by claim 12, wherein Applicant is respectfully placed on notification that a rejection under 35 U.S.C. 112(d) may be appropriate.
For the purpose of applying art, a CD16+ cell meeting all structural limitations of the cell recited in claim 1 is interpreted as reading on the limitations of claim 12.
Claim 13 recites the limitation "the pair of CH2 domains" and “the pair of heavy chains” in line 3. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite a pair of CH2 domains or heavy chains and the structure of an antibody, under some interpretations, does not inherently require a pair of CH2 domains or heavy chains because the definition of an antibody includes antigen binding fragments (see pg. 24 in line 30 through line 8 of pg. 25 in the specification).
Further contributing the unclarity, the structure of an antibody is not particularly pointed out and distinctly claimed because the specification on pg. 28 in line 24 specifies that an “’antibody’ used herein is a specific form of a polypeptide comprising an Fc domain comprising at least one ligand binding to a domain containing, or conserving, substantial homology with at least one of the variable domains of heavy or light chain antibody of at least one kind of animal antibody.” The structure of an “antibody” is unclear because the definition of an antibody on pg. 28 in line 24, which appears to be a limiting definition (see MPEP 2111 regarding lexicography), directly contradicts the definition of an antibody as set forth on pg. 24 in line 30 through line 8 of pg. 25 which specifics that the scope of an “antibody” includes a whole antibody as well as antigen binding fragments or single chain thereof – i.e. in one portion of the specification an “antibody” is defined as having an Fc domain while in another portion of the specification an “antibody” includes Fc-less fragments.
That said, the definition of as set forth on pg. 28 in line 24 also states that the structures of an “antibody” comprising at least one ligand binding to a domain with conserved homology to at least one variable domain. Thus, it would be unclear whether infringement upon an the structure of an “antibody” only occurs when the cognate ligand is bound to the antibody or when one has a structure capable of binding to a ligand regardless of whether the ligand is present or not.
Additionally, the use of parentheses in “(or the pair of heavy chains)” renders the metes and bounds of claim 13 indefinite because it unclear whether the limitations recited in the parentheses are part of the claimed invention or are merely exemplifications.
For the purpose of applying art, claim 13 is interpreted as “wherein the recombinant polypeptide comprises a heavy and/or light chain variable domain and a pair of CH2 domains or a pair of heavy chains, and wherein the CH2 domain modifications are symmetrical or asymmetric with respect to the pair of CH2 domains or heavy chain.”
Claim 15 also recites that the recombinant polypeptide is an antibody or fragment thereof, and thus the structure of claim 15 is indefinite for the same reasons stated above regarding the unclarity of the metes and bounds of the term “antibody.” Additionally, claim 15 recites that the polypeptide comprises the modified CH2 domain “as defined in any of claims 1 to 6 or the Fc region as defined in claim 14” however claim 6 has been canceled and it is unclear whether claim 15 is intended to be a multiple dependent claim (in which case the preamble should properly recite “the composition according to any one of claims 1-5 or 14”). Further contributing to the unclarity of the metes and bounds of claim 15 and interpretation of the scope of an “antibody”, claim 15’s list of “antibodies” comprise constructs which do not comprise an heavy and/or light chain variable domain such as aflibercept and alefacept.
For advancing prosecution on the merits, claim 15 is interpreted with the scope of “the composition of claim 1, wherein the recombinant polypeptide comprises a ligand binding domain selected from the ligand binding domain of any of the following: Abagovomab….”
Claim 48 is indefinite because it is unclear whether the individual in need thereof is a structural requirement of the claimed invention. For example, there are no positively recited structures conferred to the NK cell by the phrase “allogeneic with respect to an individual in need thereof.” Indeed, to have the quality of being “allogeneic” the presence of a second biological structure is required. Some skilled artisan would argue that claim 48 therefore requires the limitation of “an individual” to which the NK cell is allogeneic – i.e. claim 48 is limited a composition comprising said NK cell and an individual to which the NK cell is allogeneic. Applicant is respectfully placed on notification that a rejection under 35 U.S.C. § 101 for claiming a Human Organisms may be appropriate if the intended scope of claim 48 requires the structure of an individual in need thereof to which the NK cell is allogeneic. Other skilled artisans would argue that the structure of said individual is not a required limitation of the claim.
For advancing prosecution, any NK cell attached (i.e. covalently or non-covalently) to the described recombinant polypeptide is interpreted as also reading on the limitations of instant claim 48.
Claims 49, 50, and 51 recite “preferably a CD16+/NK cell allogeneic with respect to an individual in need thereof[.]” The term “preferably” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Additionally, the limitation of “allogeneic with respect to an individual in need thereof” is indefinite for the same reasons set forth supra (i.e. does the claimed subject matter require the structure of an individual?).
Claims 49, 50, and 51 are interpreted, for the sake of applying art, as not requiring the structure of an individual to which the cell is allogeneic.
Claims 3-4, 11, 14, 17, and 34 are rejected by virtue of their dependency.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 and 14 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Insofar as claim 2 has been interpreted as not requiring the limitations of SEQ ID NO: 1, as set forth supra, claim 2 does not further limit the scope of claim 1.
Claim 14 recites the polypeptide of claim 1 comprises a human IgG1 Fc region comprising the modified CH2 domain. On pg. 29 in line 28, “Fc region” is defined as “all or part of an antibody Fc fragment.” Thus, since the structure of claim 1 already requires a modified human wild-type IgG1 CH2 and an “Fc region” may be part of an antibody Fc fragment, claim 14 does not further limit claim 1 since the “modified human wild-type IgG1 CH2” is, by the definition set forth in the specification, already an Fc region.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 11-14, 17, 19, 34, 36, and 48-51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kellner et al. Leukemia. 2013. 27: 1595-1598, cited herewith; evidenced by Horton et al. Cancer Res. 2008. 68(19):8049-8057, cited herewith and Kabat et al. (1991). Sequences of Proteins Of Immunological Interest. Vol. I (Fifth Ed). USDA, cited herewith.
Kellner incubated antibody MOR208 (XmAb5574) with NK cells and target cells. (see Fig. 1b and 1c on pg. 1595, Fig. 2 and text on pg. 1596, first col. on pg. 1597, and fourth ¶ of the appended Supplementary Material and Methods “NK cell activation assay”).
MOR208 inherently comprises an anti-CD19 ligand binding domain (see Kellner in the second col. on pg. 1595) and a human IgG1 CH2 domain consisting of S239D and I332E mutations, pertaining to instant claim 14. (see Horton on pg. 8050 in the second ¶ of the first col. and pg. 8051 in the first col.; and citation of Horton by Kellner on pg. 1595 in the second col., reference 7). Note well, while Horton does not explicitly recite that S239D and I332E are in the CH2 domain or that the CH2 domain comprises sequence positions 231-340 according to EU, but the only native residues that are S239 and I332 in the human IgG1 Fc region occur in the CH2 domain and an human IgG1 Fc necessarily comprises a CH2 having positions 231-340 according to EU (see, e.g., Kabat on pg. 680). Thus, the S239D and I332E mutations of MOR208 are necessarily in the CH2 domain, and MOR208, having human IgG1 Fc portion, necessarily comprises a CH2 domain with sequence positions 231-340 according to EU.
Claims 1, 19, and 36 recite compositions “comprising” CD16+ / NK cells and a recombinant polypeptide, thus the presence of additional materials, i.e. target cells, falls within the scope of the claims.
Claims 1 and 19 also recite limitations of the polypeptide as “capable of binding to” and “non-covalently bound to” the FcγRIII (CD16) surface protein, and in claim 36 the polypeptide is claimed as “capable of binding to said NK cell”. MOR208 is inherently capable of binding to FcγRIIIa / NK cells, indeed the S239D and I332E mutations augment its ability to do so (see e.g. Horton in Fig. 1 on pg. 8051). Regarding “non-covalently bound” to FcγRIIIa, the NK killer cells of Kellner comprise FcγRIIIa (see e.g. Fig. 2 d), Kellner shows evidence that the composition of NK cells, MOR208, and target cells resulted in lysis / ADCC of the target cells, and Kellner explains that lysis is resultant from FcγR receptor-antibody interaction (see pg. 1595 in the last ¶ of the first col. spanning the second col.). Kellner does not explicitly state that the NK cells kill the target cells through non-covalently binding MOR208 by their FcγRIIIa, however the evidence tends to indicate that Kellner’s composition of NK cells, MOR208, and target cells comprises MOR208 non-covalently bound to the FcγRIIIa receptor of at least one NK cells. Insofar as applicant wishes to contest this assertion, it is applicant’s burden to show that MOR208 is not non-covalently bound to an FcγRIIIa receptor of the NK cells under Kellner’s disclosed conditions of expression and purification. See In re Best, 195 USPQ 430, 433 (CCPA 1977); In re Marosi, 218 USPQ 289, 292-293 (Fed. Cir. 1983); In re Fitzgerald et al., 205 USPQ 594 (CCPA 1980).
In conclusion, Kellner’s composition of NK cells, MOR208 and target cells anticipates instant claims 1, 14, 19, and 36. Additionally the NK cell of instant claim 48 is anticipated on the same grounds that the composition of Kellner necessarily comprises MOR208 non-covalently attached to the NK cell through FcγRIIIa. As set forth in the rejections under 35 U.S.C. 112(b) supra, instant claim 2 is interpreted as not requiring additional structural features over the CH2 domain of instant claim 1 and is therefore anticipated on the same grounds. As previously described, the evidence tends to indicate that MOR208 induces NK cell killing through non-covalent binding to FcγRIIIa on the surface of NK cells, thus instant claim 3 is anticipated. Regarding instant claim 11, no other mutations to the CH2 MOR208 besides S239D and I332E are described, thus in absence of evidence to the contrary, MOR208 inherently comprises a CH2 domain consisting of mutations S239D and I332E. Regarding instant claim 12, “allogeneic with respect to an individual” is interpreted as not conferring any additional structure differences to the product describe in claim 1, therefore instant claim 12 is also anticipated on the same grounds. Regarding instant claim 13, Kellner and Horton do not explicitly state whether the S239D and I332E of MOR208 are symmetrical or asymmetrical, however since there are no other structural conformations MOR208 is necessarily at least one of symmetrical or asymmetrical.
Kellner describes NK cell, target cell, and MOR208 compositions as being incubated with antibodies in a volume of 1 mL for 20 hrs. The culturing conditions described by Kellner require an excipient capable of sustaining NK cell viability for the indicated time (e.g. isotonic solution). Therefore, Kellner anticipates instant claims 17 and 34.
Instant claims 49, 50, and 51 are interpreted as having the scope of the first and second as part of the same composition and/or separate compositions, and claims 49, 50, and 51 are generic as to whether the polypeptide is bound to the CD16+ / NK cell. Moreover, the terms “kit” and “allogeneic” do not confer any structural differences over the compositions comprising NK cells, MOR208, and target cells described by Kellner. Thus, instant claims 49, 50, and 51 are anticipated on the same grounds.
Claims 1-5, 7, 12-15, 17, and 49 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Moore et al. mAbs. 2010. 2(2):181-189.
Moore determined the capacity for different Fc variants of Ocrelizumab for inducing ADCC in cultures comprising target cells and PBMCs genotyped for FcγRIIIa (pg.185, 1st col., 1st ¶; Table 2 on pg. 184; and pg. 187 in the 2nd full ¶ of the 2nd col.). One of the Fc variants comprises S239D/I332E (DE) combined with H268F/S324T (FT) (see pg. 182 in the last ¶ spanning pg. 183 and Table 2). Ocrelizumab is a humanized IgG1 antibody having an anti-CD20 ligand binding domain and the mutations were introduced to the CH2 domain (see pg. 182 in the 1st ¶ of the 2nd col.).
The Ocrelizumab DE + FT variant is inherently capable of binding to FcγRIIIa, indeed the DE + FT mutations augment its ability to do so (see e.g. Moore in Table 2 on pg. 185). Regarding “non-covalently bound” to FcγRIIIa, the PBMCs of Moore comprise FcγRIIIa as evidenced by genotyping discussed above; Moore shows evidence that the composition of PBMCs, Ocrelizumab DE + FT, and target cells resulted in lysis / ADCC of the target cells; and Moore explains that ADCC is resultant from FcγR receptor-antibody interaction (see, e.g. pg. 186 in the last ¶ of the first col. spanning the second col. – “The FT variant possesses not only improved complement activity but FcγR affinities favorable for ADCC and ADCP.”) Moore does not explicitly state that the PBMCs kill the target cells through non-covalently binding Ocrelizumab DE + FT by their FcγRIIIa, however the evidence tends to indicate that Moore’s composition of PBMCs, Ocrelizumab DE + FT, and target cells comprise Ocrelizumab DE + FT non-covalently bound to the FcγRIIIa receptor of at least one PBMC. Insofar as applicant wishes to contest this assertion, it is applicant’s burden to show that Ocrelizumab DE + FT is not non-covalently bound to an FcγRIIIa receptor of the PBMCs under Moore’s disclosed conditions of expression and purification. See In re Best, 195 USPQ 430, 433 (CCPA 1977); In re Marosi, 218 USPQ 289, 292-293 (Fed. Cir. 1983); In re Fitzgerald et al., 205 USPQ 594 (CCPA 1980).
In conclusion, instant claims 1-5, 7, 12-15, 17, and 49 are anticipated by Moore.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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.
Claims 1-5, 7, 12-15, 17, 19, 34, 36, and 48-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 18/551,156 in view of Moore et al. mAbs. 2010. 2(2):181-189; as evidenced by Caaveiro et al. Immunol Rev. 2015. 268:201-221.
Claim 1 of ‘156 sets forth an immune cell comprising an Fc receptor on its surface comprising a hybrid molecule “grafted” onto the Fc receptor, wherein the hybrid molecule comprises an Fc fragment. In claim 3, ‘156 teaches that the Fc receptor is FcγRIII, i.e. the immune cell is a FcγRIII + cell. In claims 8-9, ‘156 teaches that the Fc fragment is a human IgG1 fragment comprising S239D, H268F, S324T, and I332E. In claim 12, ‘156 teaches NK cell, relating to instant claims 19, 34, 36, 48, 50, and 51. A “hybrid molecule is grafted onto the Fc receptor” is defined as “the immune cell expresses at least one Fc receptor on its surface and that a hybrid molecule as defined here is bound to the Fc via an Fc fragment.” (specification pg. 3 in lines 28-30).
‘156 teaches a CD16+ / NK cell comprising a modified human IgG1 Fc fragment comprising S239D, H258F, S324T, and I332E mutations bound to the cell’s FcγRIII (CD16), however ‘156 does not teach that the Fc fragment is bound to a ligand binding domain.
Moore determined the capacity for different Fc variants of Ocrelizumab for inducing ADCC in cultures comprising PBMCs genotyped for FcγRIIIa and target cells (pg.185, 1st col., 1st ¶; Table 2 on pg. 184; and pg. 187 in the 2nd full ¶ of the 2nd col.). One of the Fc variants comprises S239D/I332E (DE) combined with H268F/S324T (FT) (pg. 182 in the last ¶ spanning pg. 183 and Table 2). Ocrelizumab is a humanized IgG1 antibody having an anti-CD20 ligand binding domain and the mutations were introduced to the CH2 domain (pg. 182 in the 1st ¶ of the 2nd col.). Moore teaches that NK cells are the primary effectors for ADCC (pg. 185 in the first col.).
The Ocrelizumab DE + FT variant is inherently capable of binding to FcγRIIIa, indeed the DE + FT mutations augment its ability to do so (see e.g. Moore in Table 2 on pg. 185). Regarding “non-covalently bound” to FcγRIIIa, the PBMCs of Moore comprise FcγRIIIa as evidenced by genotyping discussed above; Moore shows evidence that the composition of PBMCs, Ocrelizumab DE + FT, and target cells resulted in lysis / ADCC of the target cells; and Moore explains that ADCC is resultant from FcγR receptor-antibody interaction (see, e.g. pg. 186 in the last ¶ of the first col. spanning the second col. – “The FT variant possesses not only improved complement activity but FcγR affinities favorable for ADCC and ADCP.”) Moore does not explicitly state that the PBMCs kill the target cells through non-covalently binding Ocrelizumab DE + FT by their FcγRIIIa, however the evidence tends to indicate that Moore’s composition of PBMCs, Ocrelizumab DE + FT, and target cells comprise Ocrelizumab DE + FT non-covalently bound to the FcγRIIIa receptor of at least one PBMC. Insofar as applicant wishes to contest this assertion, it is applicant’s burden to show that Ocrelizumab DE + FT is not non-covalently bound to an FcγRIIIa receptor of the PBMCs under Moore’s disclosed conditions of expression and purification. See In re Best, 195 USPQ 430, 433 (CCPA 1977); In re Marosi, 218 USPQ 289, 292-293 (Fed. Cir. 1983); In re Fitzgerald et al., 205 USPQ 594 (CCPA 1980).
In conclusion, instant claims 1-5, 7, 12-15, 17, and 40 are taught by Moore.
It would have been prima facie to a person of ordinary skill in the art to combine the teachings of ‘156 regarding a modified Fc comprising S239D, H258F, S324T, and I332E mutations bound to the FcγRIII of a NK cell with the teachings of Moore regarding activating ADCC activity of FcγRIIIa (CD16) positive cells in culture against target cells using an antibody comprising the same mutations. The skilled artisan would have been motivated to construct the modified Fc of ‘156 with a ligand binding domain because said artisan would recognize that such a construct, as evidenced by Moore, would be useful for killing target cells (e.g. cancer cells) through activating ADCC when the construct is bound to a NK cell. The person having ordinary skill would have had a reasonable expectation of success in doing so in view of the level of skill, state of the art as evidenced by Moore, and explicit teaches of ‘156 and Moore. In doing so, one would necessarily have arrived at the claimed invention. Particularly of note, the nature of binding of the Fc part of an antibody to an FcγR is through non-covalent interactions (see, e.g., Caaviero in Fig. 5 on pg. 208 and citation of literature not relied upon for rejection).
Claims 1-5, 7, 12-15, 17, 19, 34, 36, and 48-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 18/551,129 in view of Moore et al. mAbs. 2010. 2(2):181-189; as evidenced by Caaveiro et al. Immunol Rev. 2015. 268:201-221.
Claim 1 of ‘129 sets forth a hybrid molecule comprising an Fc fragment. In claims 6-7, ‘129 teaches that the Fc fragment is a human IgG1 fragment comprising S239D, H268F, S324T, and I332E.
‘129 teaches a modified human IgG1 Fc fragment comprising S239D, H258F, S324T, and I332E mutations, however ‘156 does not teach that the Fc fragment is bound to a ligand binding domain or the FcγRIII receptor of a CD16+ / NK cell.
Moore determined the capacity for different Fc variants of Ocrelizumab for inducing ADCC in cultures comprising PBMCs genotyped for FcγRIIIa and target cells (pg.185, 1st col., 1st ¶; Table 2 on pg. 184; and pg. 187 in the 2nd full ¶ of the 2nd col.). One of the Fc variants comprises S239D/I332E (DE) combined with H268F/S324T (FT) (pg. 182 in the last ¶ spanning pg. 183 and Table 2). Ocrelizumab is a humanized IgG1 antibody having an anti-CD20 ligand binding domain and the mutations were introduced to the CH2 domain (pg. 182 in the 1st ¶ of the 2nd col.). Moore teaches that NK cells are the primary effectors for ADCC (pg. 185 in the first col.), relating to instant claims 19, 34, 36, 48, 50, and 51.
The Ocrelizumab DE + FT variant is inherently capable of binding to FcγRIIIa, indeed the DE + FT mutations augment its ability to do so (see e.g. Moore in Table 2 on pg. 185). Regarding “non-covalently bound” to FcγRIIIa, the PBMCs of Moore comprise FcγRIIIa as evidenced by genotyping discussed above; Moore shows evidence that the composition of PBMCs, Ocrelizumab DE + FT, and target cells resulted in lysis / ADCC of the target cells; and Moore explains that ADCC is resultant from FcγR receptor-antibody interaction (see, e.g. pg. 186 in the last ¶ of the first col. spanning the second col. – “The FT variant possesses not only improved complement activity but FcγR affinities favorable for ADCC and ADCP.”) Moore does not explicitly state that the PBMCs kill the target cells through non-covalently binding Ocrelizumab DE + FT by their FcγRIIIa, however the evidence tends to indicate that Moore’s composition of PBMCs, Ocrelizumab DE + FT, and target cells comprise Ocrelizumab DE + FT non-covalently bound to the FcγRIIIa receptor of at least one PBMC. Insofar as applicant wishes to contest this assertion, it is applicant’s burden to show that Ocrelizumab DE + FT is not non-covalently bound to an FcγRIIIa receptor of the PBMCs under Moore’s disclosed conditions of expression and purification. See In re Best, 195 USPQ 430, 433 (CCPA 1977); In re Marosi, 218 USPQ 289, 292-293 (Fed. Cir. 1983); In re Fitzgerald et al., 205 USPQ 594 (CCPA 1980).
In conclusion, instant claims 1-5, 7, 12-15, 17, and 40 are taught by Moore.
It would have been prima facie to a person of ordinary skill in the art to combine the teachings of ‘129 regarding a modified Fc comprising S239D, H258F, S324T, and I332E mutations with the teachings of Moore regarding activating ADCC activity of natural killer FcγRIIIa (CD16) positive cells in culture against target cells using an antibody comprising the same mutations. The skilled artisan would have been motivated to construct the modified Fc of ‘129 with a ligand binding domain by recognizing that the purpose of such a construct, as evidenced by Moore, when bound to a NK cell, is to lyse target cells through ADCC. The person having ordinary skill would have had a reasonable expectation of success in doing so in view of the level of skill, state of the art as evidenced by Moore, and explicit teaches of ‘129 and Moore. In constructing and using the modified Fc of ‘129 with a ligand binding domain in view of Moore, one would necessarily have arrived at the claimed invention. Particularly of note, the nature of binding of the Fc part of an antibody to an FcγR is through non-covalent interactions (see, e.g., Caaviero in Fig. 5 on pg. 208 and citation of literature not relied upon for rejection).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Oganesyan et al. (Molec Immunol. 2008. 45:1872-1882) explains that S239D/A330L/I332E mutations may introduce additional hydrophobic contacts, hydrogen bonds, and/or electrostatic interactions (see Abstract). In GASDALIE mutated Fc, S239D and I332E form salt bridges with FcγRIIIa (Ahmed. J Struct Biol. 2016. 194:78-89; see Fig. 2 on pg. 85).
Applicant is advised that should claim 50 be found allowable, claim 51 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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/B.K.S./Examiner, Art Unit 1644
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683