Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Status of the Claims
1. Claims 1-6 are the original claims filed on 8/21/2023. In the Response of 6/16/2026, claims 1-2 and amended and new claim 7 is added.
Claims 1-7 are all the claims for this application.
The Office Action contains new grounds for objection.
The Office Action is final.
Priority
2. USAN 18/453,107, filed 08/21/2023, is a Continuation of 16/932,588, filed 07/17/2020, now abandoned, 16/932,588 is a Continuation of 15/447,622, filed 03/02/2017, now abandoned and having 1 RCE-type filing therein,
15/447,622 is a Continuation of 14/374,612, filed 07/25/2014, now abandoned and having 1 RCE-type filing therein, 14/374,612 is a National Stage entry of PCT/GB2013/ 050164, International Filing Date: 01/25/2013, claims foreign priority to GB 1201314.0, filed 01/26/2012. Applicants claim to benefit of priority for the claimed method invention as of the filing date 1/26/2012 for foreign priority application GB 1201314.0 is granted.
Information Disclosure Statement
3. As of 8/13/2026, a total of two (2) IDS are filed: 8/21/2023 (7 pages); and 8/21/2023 (10 pages). The corresponding initialed and dated 1449 is considered and of record.
4. The IDS dated 8/21/2023 (12 pages) is not entered. Applicants are advised to re-file the IDS on a proper PTO/SB/08c form.
Withdrawal of Objections
Specification
5. The objection to the disclosure because of informalities is withdrawn.
a) The specification is amended to rectify the improper use of the terms GenBank, Tween, Sepharose, GraphPad, Spectramax, Rituxan, Yervoy (misspelled “Yermoy”), which is a trade name or a mark used in commerce.
b) The specification is amended to correct the misspelling of “Yervoy” from “Yermoy.”
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
6. The rejection of Claim 2 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn. Claim 2 is amended to delete the entirety of the parenthetical text for the phrase “(renal cell)”.
Claim Rejections - 35 USC § 112(d)
7. The rejection of Claim 2 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent is withdrawn. Claim 2 is amended to delete the phrase “(renal cell)”.
Rejections Withdrawn-in-part/ Maintained-in-part
Claim Rejections - 35 USC § 112(a)
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.
Written Description
8. The rejection of Claims 1-7 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 is:
Withdrawn-in-part: Claims 1-7 are amended to recite in claim 1(a)and (c in-part) the EndoS sequence of SEQ ID NO: 1 or 2.
Maintained-in-part: Claims 1-7 are amended to recite in claim 1(b) and (c in-part) a variant of the EndoS sequence of SEQ ID NO: 1 or 2 having at least 70% identity.
Response to Arguments
(A) Claim interpretation
The specification teaches examples of hypothetical variants based on a percent identity to SEQ ID NO: 1 or 2 as previously discussed at [0106]. The specification does not disclose an example of an allelic variant much less one tested in the method of treating any cancer. The specification does not disclose the residue(s) that are suitable to deletion, modification and/or addition that comprises the percent variance yet retain(s) the enzyme activity.
[0106] Variant polypeptides are those for which the amino acid sequence varies from that in SEQ ID NO: 1 or SEQ ID NO: 2, but which retain the same essential character or basic functionality as EndoS. The variant polypeptides may therefore display IgG endoglycosidase activity. Typically, polypeptides with more than about 50%, 55%, 60% or 65% identity, preferably at least 70%, at least 75%, at least 80%, at least 85%, at least 90% and particularly preferably at least 95%, at least 97% or at least 99% identity, with the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 are considered variants of the protein. Such variants may include allelic variants and the deletion, modification or addition of single amino acids or groups of amino acids within the protein sequence, as long as the peptide maintains the basic functionality of EndoS. The identity of variants of SEQ ID NO: 1 or SEQ ID NO: 2 may be measured over a region of at least 100, at least 250, at least 500, at least 750, at least 800, at least 850, at least 900, at least 950, at least 955 or more contiguous amino acids of the sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2, or more preferably over the full length of SEQ ID NO: 1 or SEQ ID NO: 2.
The specification teaches examples of preferred hypothetical variants based on the necessity of specific amino acid residues being present or conserved in order to retain enzymatic activity as previously discussed at [0107]. Where the specification teaches preferably, the variant of SEQ ID NO:1 contains Glu-199 of SEQ ID NO:1 and the variant of SEQ ID NO:2 contains Glu-235 of SEQ ID NO:2, neither of these residues are recited in the amended claims for the variants.
[0107] Variants of the amino acid sequence of SEQ ID NO: 1 preferably contain residues 191 to 199 of SEQ ID NO: 1, i.e., Leu-191, Asp-192, Gly-193, Leu-194, Asp-195, Val-196, Asp-107, Val-198, Glu-199, of SEQ ID NO:1 (which corresponds to residues 227 to 235 of SEQ ID NO:2, i.e. Leu-227, Asp-228, Gly-229, Leu-230, Asp-231, Val-232, Asp-233, Val-234 and Glu-235 of SEQ ID NO:2), These amino acids constitute a perfect chitinase family 18 active site, ending with glutamic acid. The glutamic acid in the active site of chitinases is essential for enzymatic activity. Most preferably, therefore, the variant of SEQ ID NO:1 contains Glu-199 of SEQ ID NO:1 and the variant of SEQ ID NO:2 contains Glu-235 of SEQ ID NO:2.
The specification does not support the myriad endoS enzymes having the full breadth of attributes required of the instant claimed method to place Applicants in full possession of the method invention. The interpretation encompasses a genus of EndoS structures beyond those taught in the specification. Because applicant seeks patent protection for all such endoS agents, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Disclosure in the Specification
The specification teaches hypothetical Examples 2-4 for the in vivo use of the endoS therapy in Examples 2-3, and extracorporeal use in Example 4 followed by a HER2-specific, glycol-engineered antibody.
The specification does not nearly test the genus of all possible endoS enzymes but only that of a protein enzyme for SEQ ID NO: 1 from S. pyogenes.
The specification does not nearly test the genus of all possible endoS variants or fragments much less that of any such sequence corresponding to SEQ ID NO:1 in any the in vitro bioassays for measuring reduced, non-specific serum Ig binding to FcR.
Applicants specification does not support the genus of endoS enzymes that can be used in vitro, in vivo, or extracorporeal that would deglycosylate any Ig in order to effectuate an anti-cancer therapeutic effect for any endo—resistant antibody, in vivo.
(B) Applicants have not addressed the outstanding technical and legal arguments presented in the Office Action of 3/17/2026 excerpted herein below.
The response is incomplete.
f) Predictability in the Art:
Applicants own specification discusses the caveats of enzyme-mediated approaches to reducing IgG binding to FcR at p. 4, lines 6-17:
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Applicants own specification teaches the importance and complexities of the kind of enzyme used, the resistance of the therapeutic antibody to that enzyme and the timing of the application of the enzyme on p. 4, lines 23-27:
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Applicants own specification narrows the success of the invention to endoS enzymes on p. 8, lines 16-20 and the working embodiments discussed above:
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Finally, and with respect to claims encompassing variants of any kind of enzyme much less that for the S. pyogenes enzyme of SEQ ID NO: 1, the decision from Novozymes is pertinent. In Novozymes A/S v. DuPont Nutrition Biosciences APS, Case No. 12-1433 (Fed. Cir., July 22, 2013) the Federal Circuit noted that the relevant question is not whether a person of ordinary skill in the art would have been enabled to identify specific variants within the scope of the claims, but instead, whether the specification actually discloses those variants to a person of skill in the art. To demonstrate actual possession of the claimed variants, "Novozymes [needed] to confirm its predictions by actually making and testing individual variants or at least identifying subclasses of variants that could be expected to possess the claimed properties."
Thus, based on the limited number of EndoS enzymes disclosed in the specification that have the attributes (structure/function correlation) for at least a reasonable scope of the claimed method invention, that being in vitro, and effecting non-specific, endogenous Igs from blocking or competing for binding with intended or desired antibody binding, the ordinary artisan would conclude that applicants were not in possession of the full scope of the invention at the time of filing.
The rejection is maintained.
Rejections Maintained
Claim Rejections - 35 USC § 112(a)
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.
Enablement
9. The rejection of Claims 1-7 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is maintained.
(A) Applicants allege there is no undue burden in selecting a suitable enzyme from within this group. Similarly, there is no undue burden required to determine an appropriate time interval for step (ii) of the method of claim 1. The specification teaches that the time interval is to provide sufficient time for the enzyme to act to reduce Fc receptor binding by endogenous antibodies (such that the administered trastuzumab has less competition). It is within the routine work of the skilled person to determine a suitable interval for this purpose, e.g. by testing enzyme activity on a serum sample.
Response to Arguments
Based on the unlimited number of EndoS enzymes recited in the claims and taught in the specification that allegedly possess the claimed attributes (structure/function correlation): as shown, in vitro, and effecting non-specific, endogenous Igs from blocking or competing for binding with intended or desired unlimited oligomannose-type glycated trastuzumab antibodies, the ordinary artisan could reasonably conclude the full scope of the invention at the time of filing requires unduly burdensome amounts of experimentation. See the extended analysis of the claim scope from the written description herein above.
"[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)). The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, the method is unpredictable and the experimentation left to those skilled in the art is unnecessarily and improperly extensive and undue. See Amgen, Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F,2d 1200, 18 USPQ 1016 (Fed. Cir. 1991) at 18 USPQ 1026 1027 and Ex parte Forman, 230 USPQ 546 (BPAI 1986).
(B) Applicants allege Example 1 demonstrates the endoglycosidase enzymes of the claims (based on SEQ ID NO: 1 and 2) are inherently poor at cleaving oligomannose-type glycans and so such glycans are generally suitable for use in accordance with the presently claimed invention; Example 1 of the application as filed demonstrates that modifying the monoclonal antibody CIIC1 (mAb IgG CIIC1) with an oligomannose-type glycan does not impact its binding capabilities (see page 42 lines 9-28, and Figure 7 of the originally filed application). The Example goes on to show that the combination of EndoS and the oligomannose-type mAb IgG CIIC1 results in increased Fc-receptor binding by the antibody with a 50% receptor saturation achieved at approximately 0.05 pM of mAb IgG CIIC1 (see page 43 lines 3-7 of the originally filed application).
Response to Arguments
The CIIC1 antibody relied on by Applicants as demonstrative of the glycation properties for the claimed antibody of the invention, namely, trastuzumab, after the set time interval of the method, is incongruous with the actual claims. CIIC1 antibody is a monoclonal antibody that targets the C1 epitope (triple helical positions 358–364) of collagen type II (see www.novusbio.com/PDFs5/NBP3-11227.pdf product data sheet) and has no relationship to trastuzumab (anti-HER2). Applicants have yet to demonstrate where the specification teaches the oligomannose-type glycation of the trastuzumab antibody (claim 1) comprising at least 5 mannose residues (claim 4), and comprising the glycans (a)-(d) of claim 5.
Under Rasmussen v. Smith Klein Beecham Corp., 413 F.3d 1318, 1325 (Fed. Cir. 2005) "If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions' consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked."
The rejection is maintained.
Claim Rejections - 35 USC § 103
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 through the invention is not identically disclosed or described as set forth in section 102 of this title, 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 negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
10. The rejection of Claims 1-7 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Preither et al. (Molec. Immunol. 43(8):183-1193 (2006); IDS 8/21/2023) in view of Nandakumar et al. (TRENDS IN IMMUNOLOGY, ELSEVIER LTD. TRENDS JOURNALS, GB, vol. 29, no. 4, 6 March 2008 (2008-03-06), pages 173-178); IDS 8/21/2023) and Hodoniczky et al (Biotechnol. Prog. 2005,21, 1644−1652) is maintained.
(A) Applicants allege the cited prior art of a method for treating cancer comprising administering EndoS and subsequently administering trastuzumab comprising oligomannose-type glycan modifications, let alone with the specific EndoS amino acid sequences recited in amended claim 1. Furthermore, the cited prior art does not provide any experimental data regarding the interactions of EndoS, an oligomannose-type modified antibody and serum antibodies.
Response to Arguments
In response to applicant's argument that the references do not teach the method steps of claim 1, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In response to applicant’s arguments that the cited prior art does not provide any experimental data regarding the interactions of EndoS, an oligomannose-type modified antibody and serum antibodies, none of the references teach the unpredictability of the art nor do Applicants identify a single aspect of the claimed invention being improved, unexpected or surprising.
(B) Applicant considers each of the references for what they teach.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
New Grounds for Objection
Claim Objections
11. Claim 5(b) is objected to because of the following informalities:
Amend Claim 5(b) to recite “(b) each of the glycans of the Fc domain contains MansGlcNAci, .
Appropriate correction is required.
Conclusion
12. No claims are allowed.
13. THIS ACTION IS MADE FINAL. 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.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached on Mon-Fri 9 AM-5 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 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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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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