DETAILED ACTION
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 .
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.
Withdrawn Objections
The objections to the specification are withdrawn in response to the amendments.
The objections to the claims are withdrawn in response to the amendments.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2020/050798, filed 09/15/2020, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/900,892, filed 09/16/2019.
Status of the Claims
Claims 1-21 are pending; claims 2-21 are amended; no claims are canceled; no claims are withdrawn. Claims 1-21 are examined below.
Maintained Rejections
Claim Rejections - 35 USC § 112
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.
Claims 1-21 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 and 10 and its dependent claims require first beads having an affinity for the F(ab’)2 region of an antibody-drug conjugate (ADR) and second beads having an affinity for the Fc fragment of the ADR. Dependent claims 7 and 16 require an F(ab’)2 fragment having affinity for the F(ab’)2 region of the ADR, and dependent claims 8 and 17 require an F(ab’)2 fragment having affinity for the Fc fragment of the ADR.
The specification does not describe which amino acid residues, nucleic acid residues, or other molecular components are present in the genus of agents encompassed by claims 1-21. The specification fails to disclose the structures common to all members of the genus and fails to provide sufficient specific examples of agents to be used. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
Regarding the claimed scope that includes antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited beads and F(ab’)2 fragments can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of beads and antibodies and variants, fragments or derivates of the antibodies of the claims.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the full genus of beads and F(ab’)2 fragments encompassed by the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of encompassed F(ab’)2 fragments.
Although the specification discloses one example of an F(ab')2 fragment having affinity for the Fc region and one example of an F(ab')2 fragment having affinity for the F(ab')2 region (“AffiniPure F(ab')2 Fragment Goat Anti-Human IgG Fcγ Fragment Specific, and F(ab')2 Fragment Specific capture reagents were purchased from Jackson ImmunoResearch (PA, USA)” (paragraph 45), these are not sufficient to describe the genus of beads and beads comprising F(ab')2 fragments specific for the F(ab')2 and Fc regions of the ADC encompassed by the claims.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of each genus of claimed agents, i.e.; beads having an affinity for the F(ab’)2 fragment, beads having an affinity for the Fc fragments, F(ab’)2 fragments having an affinity for the F(ab’)2 fragments and F(ab’)2 fragments having an affinity for the Fc fragment. Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Su et al. (WO 2017205741 A1) (Cite No. 1 of IDS filed 3/15/2022) ("Su").
Regarding claim 1, Su teaches a method for analyzing whether, in an antibody-drug conjugate (ADC) (“[m]ethods to rapidly and accurately detect, characterize, measure, and quantify site-specific antibody drug conjugates” Abstract) having a partner molecule attached to the Fc fragment of the antibody (“ADCs with site-specific conjugated drug moieties in the Fc region” page 3 lines 19-20), a transformation has occurred in the partner molecule (“Either one or both of the drug and digested antibody component(s)/fragment are then analyzed by chromatography/ spectrometry to determine characteristics of the ADC, which may include, but are not limited to… the drug concentration and/or the average DAR of the ADC” page 72 lines 16-21), comprising the steps of: a. capturing the ADC on first beads having an affinity for the F(ab')2 region of the antibody (“affinity capture LC-MS F(ab')2 assay incorporates affinity capture of ADCs via binding to the Fab region. The affinity capture of ADCs via binding to the Fab region” page 3 lines 6-7, “The affinity capture media may include at least one of bead- or resin-supported Protein A/G, target antigen-paramagnetic bead capture media” page 5 lines 33-34 and page 6 line 1); b. digesting the ADC captured on the first beads in a digestion medium comprising a protease that cleaves the antibody into an F(ab')2 fragment and an Fc fragment having the partner molecule attached thereto (“followed by on-bead IdeS digestion to remove the Fc domain specifically and uniformly” page 3 lines 7-8, “The step of digesting may also be carried out while ADC is bound to the affinity capture media” page 6 lines 4-5) and optionally a deglycosylating enzyme (“These methods may also include … deglycosylating the ADC bound to the affinity capture media” page 6 lines 3-4, “EndoS is a specific endoglycosidase used to deglycosylate antibodies. Additional endoglycosidases that may be useful in the methods of this disclosure include one or more of Endo S2” page 74 lines 5-7), whereby the F(ab')2 fragment remains attached to the first beads and the Fc fragment is released. Although Su fails to use the language “F(ab')2 fragment remains attached to the first beads and the Fc fragment is released”, the teaching of capture beads binding the F(ab')2 region and followed enzyme digestion to remove the Fc domain, inherently provides the F(ab')2 fragments remaining on the bead and the release of the Fc fragment. Su further teaches e. obtaining a mass spectrometric analysis of the eluted Fc fragment having the partner molecule attached thereto, to determine if a transformation occurred in the partner molecule (“elution of an enriched, digested antibody sample from the affinity capture media, and subsequent chromatography/spectrometry analysis” page 76 lines 11-12).
Su fails to teach c. capturing the released Fc fragment having the partner molecule attached thereto on second beads having an affinity for the Fc fragment and d. eluting with an acidic eluent the Fc fragment having the partner molecule attached thereto from the second beads.
Regarding claim 10, Su teaches a method for analyzing whether, in an antibody-drug conjugate (ADC) having a first partner molecule attached to the Fc fragment of the antibody a transformation has occurred (Abstract, page 3 lines 19-20 and page 72 lines 16-21), comprising the steps of: a. capturing the ADC on first beads having an affinity for the F(ab')2 region of the antibody (page 3 lines 6-7, page 5 lines 33-34 and page 6 line 1); b. digesting the ADC captured on the first beads in a digestion medium comprising a protease that cleaves the antibody into an F(ab')2 fragment and an Fc fragment having the partner molecule attached thereto and optionally a deglycosylating enzyme, whereby the F(ab')2 fragment remains attached to the first beads and the Fc fragment is released (page 3 lines 7-8, page 6 lines 3-5, page 74 lines 5-7); and e. obtaining a mass spectrometric analysis of the eluted Fc fragment containing the first partner molecule attached thereto and, to determine if a transformation occurred in the first and second partner molecules (page 76 lines 11-12).
Su fails to teach a second partner molecule attached to the Fd' fragment of the antibody, steps c-f and obtaining a mass spectrometric analysis of the Fd' fragment having the second partner molecule attached thereto.
Davis et al. Bioanalysis, 9:20, 1535-1549, DOI: 10.4155/bio-2017-0148 Published online: 26 Oct 2017 (“Davis”). Davis teaches a method for analyzing whether, in an antibody-drug conjugate (ADC) having a first partner molecule attached to the Fc fragment of the antibody and a second partner molecule attached to the Fd' fragment of the antibody, a transformation has occurred in either the first or second partner molecule (“a middle-up LC–MS approach for DAR analysis using prelabeled capture beads and in-house fabricated slit-plates” Abstract, “each of the scFc and Fd’ subunits should contain up to one linker payload each” page 1541), comprising the steps of: a. capturing the ADC on first beads (“The slit-plates with beads containing captured and de-glycosylated ADCs” page 1537 paragraph 4); b. digesting the ADC captured on the first beads in a digestion medium comprising a protease that cleaves the antibody into an F(ab')2 fragment having the second partner molecule attached thereto and an Fc fragment having the first partner molecule attached thereto and optionally a deglycosylating enzyme (“Aliquots of 20 μl of wash buffer and 10 μl of 1 mg/ml PNGaseF were added to each sample and beads were resuspended by pipetting up and down…eluent was neutralized…Samples were…treated with 1 μl of 1 mg/ml IDeS” page 1537 paragraph 3); eluting with an acidic solvent the bead having the second partner molecule attached thereto from the first beads (“Aliquots of 100 μl of 0.1% formic acid in water (elution buffer)” page 1537 paragraph 3); f. reducing disulfide bonds in the eluted F(ab')2 to produce an Fd' fragment having the second partner molecule attached thereto (Figure 1B); and e. obtaining a mass spectrometric analysis of the eluted Fc fragment containing the first partner molecule attached thereto and the Fd' fragment having the second partner molecule attached thereto, to determine if a transformation occurred in the first and second partner molecules (Figure 3).
Davis fails to teach first beads having an affinity for the F(ab’)2 region, step b whereby the F(ab')2 fragment remains attached to the first beads and the Fc fragment is released, and steps c-e.
There were no references found that taught steps c-d of claim 1 or steps c-e of claim 10, it appears that these limitations are free of the prior art, i.e., claims 1-21 appear to be novel and unobvious over the prior art.
Response to Arguments
Applicant's arguments filed 10/8/2025 have been fully considered but they are not persuasive.
Applicant argues that “claims 1 - 21 don't encompass any agents at all. They are method claims… All of the claims of the present application are directed to methods, not antibodies. The claims do not read on antibodies… What is now claimed in the present application is methods of analysis, not antibodies… Because the Office Action only cites case law on the written description of antibodies as compositions of matter, and not method claims like those of the present application, Applicant respectfully requests withdrawal of the written description rejection” (page 7 last two paragraphs and page 8 paragraphs 1-2). However, as stated in the rejection above, the claimed methods require first beads having an affinity for the F(ab’)2 region of an antibody-drug conjugate (ADR) and second beads having an affinity for the Fc fragment of the ADR (see steps a. and c. of independent claims 1 and 10). Although the claims are to a process and not a product, the claimed process is limited by steps that use specific agents, namely the claims recite beads having specific binding affinities. The specification fails to disclose sufficient structure for the beads claimed by function (see rejection above). The lack of structural support for the beads renders the claim indefinite (see rejection above). Furthermore, contrary to Applicant’s remark that the claims are not directed to antibodies, dependent claims 7-8 and 16-17 require antibodies having specific affinities, i.e. an F(ab’)2 fragment having affinity for the F(ab’)2 region of the ADR, and an F(ab’)2 fragment having affinity for the Fc fragment of the ADR (see claims 7-8 and 16-17). Similarly to the beads of claims 1 and 10, the specification fails to provide adequate written description for the antibody fragments of claims 7-8 and 16-17, claimed by function (see rejection above). Therefore, the written description rejection is valid and maintained.
Conclusion
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.
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/Fernando Ivich/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678