DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election of Group I (drawn to a composition) and the species of E at position 332, Man9, and a lysosome-targeting chimera in the Response filed on August 7, 2026 is acknowledged.
Claims 3-5, 7-9. 11-16, 18-37, 39-52, 54-74, 76-78, 80-93, 95-116, 118-123, 125-127, 129, 130, 132, and 134-144 have been canceled.
Claims 145-149 have been added.
Claims 1, 2, 6, 10, 17, 38, 53, 75, 79, 94, 117, 124, 128, 131, 133, and 145-149 are pending.
Claims 38, 53, 79, 94, 117, 124, and 146-149 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1, 2, 6, 10, 17, 75, 128, 131, 133, and 145 are currently under consideration as they read on the elected invention.
3. 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.
4. Claims 6, 10, and 75 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.
Claim 6 recites “in the presence of a mannosidase inhibitor optionally wherein the mannosidase inhibitor is kifunensine…”. Claim 10 recites the binding polypeptide has increased affinity for binding to an Fcγ receptor …. “optionally wherein the Fcγ receptor is human FcγRIIIa”. Claim 75 recites “optionally wherein the reference polypeptide with a WT Fc domain is expressed by a cell that is cultured in the absence of kifunensine…”. The claims are indefinite in the recitation of “optional” because potential alternatives can vary (e.g. mannosidase inhibitor, Fcγ receptor, or WT Fc domain in a different cell culture) and ambiguity arises.
5. 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.
6. Claims 131 is 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.
Claim 131 depends upon claim 1. Claim 131 is drawn to a composition comprising a population of isolated glycosylated binding polypeptides each comprising an Fc domain comprising 332E (the elected species) and an N-glycan, wherein the composition comprises at least 50% Man5-9(GlcNAc)2 N-glycans by molar ration relative to all N-glycan.
The specification discloses LYTAC refers to a bifunctional molecule that comprises a region capable of binding a cell surface lysosome target receptor and a region capable of binding an extracellular domain of a target protein, including, but not limited to, secreted extracellular proteins and the extracellular domain of a membrane-bound protein. The specification further discloses that the portion of the LYTAC that can bind an extracellular domain of a target protein corresponds to the antigen-binding protein or fragment thereof (e.g. see [00182] of the specification as-filed).
There is insufficient written description in the specification as-filed of the glycosylated binding polypeptide comprising LYTAC and Fc.
The claims recite a genus glycosylated binding polypeptide comprising LYTAG and Fc as part of the invention without providing a physical structure or testable functional activity for the LYTAG.
The genus of glycoproteins are therefore extremely large. Applicant has disclosed that LYTAG is a bifunctional molecule comprises a region capable of binding a cell surface lysosome target receptor and a region capable of binding an extracellular domain of a target protein, including, but not limited to, secreted extracellular proteins and the extracellular domain of a membrane-bound protein. The specification further disclosed IgG1 antibody in the working examples. Thus Applicant has disclosed LYTAG and IgG1 but has not disclosed a glycosylated binding protein comprising LYTAG and an Fc variant.
For example, Banik et al. (Nature 2020 584:291-297) teach a glycopolypeptide ligand for CI-M6PR can be conjugated to an antibody to traffic secreted and membrane-associated protein to lysosomes (e.g. see Fig. 1a). The uptake by the lysosomes was not mediated via the Fc region of the antibody.
The claimed LYTAGs lacks a common structure essential for their function and the claims do not require any particular structural basis or testable functions to be shared by the instant glycosylated binding protein.
It does not appear based upon the limited disclosure of LYTAG or IgG antibodies 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 glycosylated binding protein comprising LYTAG and an Fc.
“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 glycosylated binding protein comprising LYTAG, there is insufficient written disclosure under 35 U.S.C. 112, first paragraph.
7. 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 (i.e., changing from AIA to pre-AIA ) 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.
8. 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.
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.
9. Claims 1, 2, 6, 10, 17, 75, 128, 131, 133, and 145 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Theranostics 2021, 11;4:1901-1917, published on January 1, 2021, reference on IDS) in view of McPherson et al. (US 2010/0184145) and Zhou et al. (Biotechnology and Bioengineering 2008, 99;3:652-665, reference on IDS) as evidenced by the instant specification on page 80 and 82 that the oligomannose was generated by treating cells with kifunensine.
Chen et al. teach I332E substitution in the Fc region of human IgG was the predominant mutations in a library screening of Fc variants with enhanced FcγRIIIa binding (e.g. see paragraph under the table in left col. in page 1908). Chen et al. teach Fc variants comprising I332E such as H268E/K326N/I332E exhibit enhanced binding to FcγRIIIa and marked increase of ADCC (e.g. see Table 1 in page 1908). Chen et al. further teach that wild type Fc displayed on α-1,6-fucosylatransferase knockout CHO-K1 (FUT8-/- CHO-K1) cells showed enhanced binding to FcγRIIIa compared with Fc displayed on FUT8-expressing CHO-K1 cells. Chen et al. teach that FcγRIIIa binding enhanced Fc variant such as H268E/K326N/I332E displayed on FUT8-/- CHO-K1 cells show synergistic effect of FcγRIIa binding suggesting the combination of defucosylation and protein mutations had an additive effect in FcγRIIIa binding enhancement (e.g. see page 1909). The antibody taught by Chen et al. is an anti-HER2 antibody trastuzumab (e.g. see right col. in page 1908).
Regarding instant claim 131 encompassing one or more of the binding polypeptides comprising a lysosome-targeting chimera (LYTAG), the instant specification discloses that he LYTAG can be an extracellular domain of a target protein corresponds to the antigen-binding protein or fragment thereof (e.g. see [00182] of the specification as-filed). Therefore, Chen’s anti-HER2 antibody would be considered a binding polypeptide comprising an antigen binding domain that binds HER2 receptor and an Fc domain. The anti-HER2 antibody would read as LYTAG and an Fc region without evidence to the contrary.
The reference teachings differ from the instant invention by not describing a composition comprising at least 50% Man5-9 (GlcNAc)2 by molar ration relative to all N-glycan.
McPherson et al. teach methods of producing antibody and Fc fusion protein with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) attributed to oligomannose-type N-glycans (e.g. see Abstract). McPherson et al. teach that the oligomannose on the antibody and Fc fusion comprises predominantly Man9 (GlcNAc)2 with diminished amounts of Man5-8(GlcNAc)2 and undetectable amount of complex-type and/or hybrid type N-glycan (e.g. see [0025]).
In working Example 1, McPherson et al. teach treating hybridoma expressing mAb with 2μg/ml kifunensine (e.g. see [0111]-[0112]) in a composition. Treatment of the cells with 0, 4, 20, 100, 500 and 2500 ng/ml kifunensine show that treatment of of 500 and 2500 ng/ml resulted in complete oligomannose structure of Man9(GlcNAc)2 (e.g. see [0144] and FIG. 15A-15F).
McPherson et al. further teach data showing that the antibodies from kifunensine treated cells contain mainly Man9(GlcNAc)2 and Man8(GlcNAc)2 (see FIGs 3C and 3F) (e.g. see [0118]). McPherson et al. teach a higher FcγRIIIA binding to TEM mAb B expressed in the presence of kifunensine as compared to the same antibody expressed in the absence of the inhibitor. The increased binding of antibody from kifunensine-treated cells to the Fc receptor correlated with the enhancement of ADCC activity of these antibodies (e.g. see [0127] and FIG.7).
Similarly, Zhou et al. teach generation of antibodies with oligomannose-type glycans that do not contain fucose by simple metabolic engineering with glycosidase inhibitor kifunensine without the need of cell line regeneration (e.g. see last paragraph in left col. in page 653). Zhou et al. teach hybridoma CHO cells expressing a human IgG1 monoclonal antibody was grown in the presence of 2μg/ml kifunensine (e.g. see right col. in page 653). Zhou et al. teach that Kifunensine is the most efficient inhibitor of α-mannosidase I, blocking N-glycan synthesis at Man8-9(GlcNAc)2 stage (e.g. see right col. under Results in page 655). Zhou et al. teach enhanced FcγRIIIA binding and enhanced ADCC for an antibody produced by CHO cells treated with at least 60 ng/ml kifunesine, where the treatment does not alter the antigen binding affinity and serum levels in vivo (e.g. see right col. in page 664). Zhou et al. teach the use of kifunensine provides considerable cost and time savings over the existing method of modulate ADCC activity as it does not require the engineering of the host cell (e.g. see last paragraph in the right col. in page 664).
It would thus be obvious to one of ordinary skill in the art at the time the instant invention was filed to combine the teachings of the references to produce antibody comprising an Fc variant comprising amino acid substitutions including H268E/K326N/I332E disclosed by Chen et al. in CHO cells treated with kifunesine as disclosed by McPherson et al. and Zhou et al. A ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success because Chen teach that FcγRIIIa binding enhanced mutations including H268E/K326N/I332E and glycoengineering of Fc without fucose have synergistic effect in enhanced FcγRIIIa binding and McPherson et al. and Zhou et al. teach the use of kifunensine (the efficient inhibitor of α-mannosidase I) is a cost and time saving method of modulate the Fc binding to FcγRIIIa and ADCC activity.
Thus, treating hybridoma cells producing antibody Fc variants including H268E/K326N/I332E with kifunensine would be expected to achieve an antibody Fc variant with oligomannose-type glycans which would enhance the Fc’s binding to FcγRIIIa further.
As evidenced by the instant specification on page 80 and 82 that the oligomannose recited in the instant was generated by treating cells with kifunensine. Given that the combined prior art teachings would result in treating the same Fc variant comprising the same I332E substitution with the same inhibitor kifunensine, the prior art Fc variant would inherently/intrinsically have the same N-glycan structure and functions as the instantly claimed Fc domain.
10. 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.
11. Claims 1, 2, 6, 10, 17, 75, 128, 131, 133, and 145 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 74, 79, 81, 99, 105, 107, and 110 of copending USSN 18/925,338 (reference application).
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 reference application are drawn to the same or nearly the same Fc domain comprising 332E and Man5-9(GlcNAc)2 N-glycan. As such, the claims in the reference application would anticipate the instant invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. No claim is allowed.
13. 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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