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 .
DETAILED ACTION
The amendment after non-final office action filed August 11, 2026 is acknowledged. Claims 1-4, 7-8, 11 were amended and claims 1-20 are pending.
Election/Restrictions
The restriction was deemed proper and made final in the previous office action. Claims 6, 15-19 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-5, 7-14 and 20 are examined on the merits of this office action.
Withdrawn Objections/Rejections
The objection to claim 8 Is withdrawn from in view of amendment of the amendment of the claims followed August 11th 2026.
The rejection of claims 1-5, 7-8, 11-13 and 20 under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter is withdrawn from in view of amendment of the amendment of the claims followed August 11th, 2026.
The rejection of claims 2 and 11 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention Is withdrawn from in view of amendment of the amendment of the claims followed August 11th, 2026.
The rejection of claim(s) 1-2, 4, 12-13 and 20 under 35 U.S.C. 102(a)(1) as being anticipated by Crispin (US20150125443 A1) is withdrawn from in view of amendment of the amendment of the claims followed August 11th, 2026.
The rejection of claim(s) 1-2, 4, 12-14, 20 under 35 U.S.C. 103 as being unpatentable over Crispin (US20150125443 A1) is withdrawn from in view of amendment of the amendment of the claims followed August 11th, 2026.
The rejection of claim(s) 3 under 35 U.S.C. 103 as being unpatentable over Crispin (US20150125443 A1) as applied to claims 1-2, 4, 12-14 and 20, in view of Rammingen (US7666582 B2) is withdrawn from in view of amendment of the amendment of the claims followed August 11th, 2026.
The rejection of claim(s) 5, 7-11 under 35 U.S.C. 103 as being unpatentable over Crispin (US20150125443 A1) as applied to claims 1-2, 4, 12-14, 20 above, in view of Bonello (EXPERT OPINION ON BIOLOGICAL THERAPY2018, VOL. 18, NO. 12, 1209–1221) and as evidenced by KEGG DRUG (Daratumumab, sequence information, accessed on 5/11/2026) is withdrawn from in view of amendment of the amendment of the claims followed August 11th, 2026.
Maintained/Revised Rejections
Claim Rejections - 35 USC § 112, First Paragraph
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 1-5, 7-14, 20 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. * Please note that the rejection has been amended substantially due to the amendment with the claims.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Scope of the claims
Claim 1 claims “A pharmaceutical combination comprising an immunoglobulin degrading enzyme and an Fc-containing protein, for use in the preparation of a medicament for treating hyperglobulinemia, wherein the enzyme reduces an adverse effect of excess immunoglobulin on a therapeutic effect of the Fc containing protein; wherein the enzyme is a mutant of WT IdeE as set forth in SEQ ID NO:2 with a deletion of the first 15, 16..19 N terminal amino acids and the Fc containing protein being an anti-CD38 antibody”.
Because the transitional term is comprises the mutant is not limited to the recited n-terminal deletion and may contain additional substitution, deletions, insertions or other sequence alterations provided the remaining claim requirements are satisfied. Accordingly, the claim has two relevant consideration (1) IdeS mutants having one of the specified end terminal durations but potentially obtaining additional sequence modifications; and (2) Antibodies that specifically recognize CD38 without limitation including one to a particular anti CD38 sequence, FC structure, mechanism of action for specifically disclosed antibody. These are all important considerations that need to be taken into account to satisfy the clinical therapeutic functional relationship.
*Please note that the term mutant, when read in light of the specification, is interpreted as encompassing a variant of wild type IdeE having truncation and or one or more amino acid substitutions. The specification describes truncation mutants lacking N and/or C terminal amino acids, substitution mutants, and mutants containing combinations of truncations and substitutions. Accordingly, “mutant” is not limited to a substitution unit but encompasses A truncation mutant along as well as a truncation meeting containing one or more additional substitutions.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification provides working examples primarily directed to specific Ide/IdeS-related enzymes, specific point mutations, specific N-terminal and C-terminal truncation mutants and a limited number of combinatorial mutants, particularly E97D_del18 and related constructs. The examples further evaluate human IgG1 cleavage activity, thermal stability, comparison versus IdeS and IdeZ, serum/plasma cleavage activity, reduced preexisting antibody recognition and enhancement of anti-CD38 antibody efficacy in mouse tumor model. The Fc-containing proteins actually exemplified in the specification are limited primarily to trastuzumab, daratumumab and IVIg. The disclosed therapeutic context is primarily limited to cleavage of human IgG/IVIg, enhancement of anti CD38 monoclonal antibody activity and limited mouse tumor model experiments.
The disclosure therefore demonstrates possession of particular IdeE variants. It does not provide actual reduction to practice representative of the full scope of claim 1, which encompasses each of the specified end terminal mutants together with additional sequence modifications permitted by the open-ended term comprises. More specifically, the experiments demonstrating reduction of the adverse effect of excess immunoglobulin on anti-CD38 therapeutic activity represents only a limited portion of the antibody scope. Claim 1 is not limited to the particular anti CD38 antibody used in that experiment. It encompasses antibodies generally that specifically recognize CD38 and satisfy the remaining functional limitation. The limited experimental evidence does not demonstrate possession of the claim functional relationship throughout the structurally and functionally broader genus.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof. Although the specification identifies particular truncation and truncation substitution mutants, claim one permits additional sequence modification and does not identify characteristics sufficient to establish which such mutants would achieve the claim functional result. Similarly, CD38 recognition alone does not identify which anti CD38 antibodies would experience adverse effects from excess immunoglobulin or have those effects reduced by the claimed mutants. Thus, the disclosure does not provide sufficient identifying characteristics demonstrating possession of the full claimed genus.
Physical/Chemical Properties
The disclosed IdeE mutants are characterized to some extent by physical and biochemical properties, including immunoglobulin cleavage activity and for particular variants stability and activity and activity in biological settings. Those data provide identifying information concerning the specifically tested variants. However, claim 1 is broader than those tested sequences. Because the mutant need only comprise one of the specified n-terminal deletions, additional sequence alterations are not excluded. The disclosure does not establish physical or chemical characteristics common to all such additionally modified mutants from which a skilled artisan would recognize that they retain the enzymatic properties necessary to produce the claimed therapeutic effect. Similarly, the physical property common to the antibody genus, recognition of CD38, does not establish that antibodies throughout the genus interact with excess immunoglobulin in the same manner or that degradation of excess immunoglobulin will have the claimed effect on their therapeutic activity.
Functional characteristics when coupled with a known or disclosed correlation between function and structure:
The specification relies heavily upon functional characteristics including IgG cleavage activity, enhanced enzymatic activity, thermal stability, reduced preexisting antibodies, enhancement of antibody therapy and treatment of hyperglobulinemia. However, the specification fails to disclose an adequate correlation between structure and function sufficient to support the broad functional genus recited in the claims. Although certain individual mutations and truncations are tested, the specification does not establish predictive structural rules governing which modifications preserve activity, which residues are critical, which substitutions are tolerated, or how one would identify additional operative variants across the full claim scope without undue experimentation. Further, the specification does not establish a sufficient correlation between the disclosed enzymatic activity and the broad therapeutic use of treating hyperglobulinemia. The examples primarily demonstrate cleavage of IgG and limited enhancement of anti-CD38 antibody activity in a mouse tumor model, but do not demonstrate possession of methods effective across the broad range of hyperglobulinemic disorders encompassed by the claims.
The examples demonstrate only that certain specifically tested mutants possess certain desired properties. The specification does not reasonably convey possession of the much broader genus encompassing broad classes of variants, Fc-containing proteins that bind CD38, and use for treatment of hyperglobulinemia.
Moreover, the examples relating to reduced immunogenicity, serum cleavage, and therapeutic enhancement are limited primarily to E97D_del18 and do not establish that the full claimed genus possesses such properties.
Method of Making
The specification provides methods for producing certain specifically disclosed mutant proteins using codon optimization, recombinant plasmids, E. coli expression, purification, and SDS-PAGE analysis. However, disclosure of methods for producing several exemplified species does not demonstrate possession of the full claimed genus. The specification does not provided sufficient guidance enabling one of ordinary skill in the art to identify or produce the full scope of immunoglobulin degrading enzymes functional variants, Fc containing proteins, combinations possessing the claimed therapeutic properties, or combination effective for treating hyperglobulinemia broadly.
Conclusion
Considering the disclosure as a whole, the specification reasonably conveys possession of the specifically disclosed IdeE mutants in particular, tested Fc containing proteins and anti-CD38 embodiment. The disclosure does not however reasonably convey possession of the full genus presently encompassed by claim 1. In particular, the combinations of IdeE mutants comprising any one of the specified n-terminal deletions, potentially together with additional sequence modifications, and antibodies generally that specifically recognize CD38, where in the degrading enzyme provides the claim reduction in the adverse effect of excess immunoglobulin on the therapeutic effect of the antibody. The specification does not provide a representative number of combinations reflecting the relevant structural and functional diversity, nor does it disclose a sufficient identifying characteristics or a known structure function correlation from which a person of ordinary skill would recognize that the experimentally observed therapeutic relationship extends throughout the claim scope.
Response to Applicant’s Arguments
Applicant argues that “Currently amended claim 1 substantially narrows each disputed limitation: the enzyme is limited to IdeE mutants of SEQ ID NO: 62 with defined N-terminal truncations, and the Fc- containing protein is restricted to CD38-specific antibodies for use in environments with excess interfering immunoglobulin. Under MPEP § 2163, disclosure of multiple representative species sharing a common structural limitation suffices to demonstrate written description support for a genus defined by that shared structural feature, which is fully satisfied here. The original specification demonstrates that Applicant possessed the full scope of the structurally defined genus now recited in amended Claim 1. Table 3 explicitly sets forth WT_dell5 through WT_del19, covering every deletion alternative recited in the claim, and paragraphs [0100]-[0107] verify their activity. Paragraphs [0114]-[0125] and Table 5 disclose additional modified variants (T24Adell8, A59L_dell8, A59V_dell8, E97D_dell8, and R280Hdell8) sharing the same N-terminal deletion architecture, illustrating representative species within the claimed genus. Paragraphs [0144]-[0145] provide full written description support for the combination of the truncated IdeE mutant with anti-CD38 antibodies to counteract excess immunoglobulin. The disclosed working examples and shared core structural feature align commensurately with the amended genus. Claims 2 and 3 further provide fallback limitations reciting closed sequence groups and a single elected species. Withdrawal of the 35 U.S.C. § 112(a) rejection is respectfully requested. Furthermore, for the purpose of compact prosecution, Applicant respectfully submits the present claims also satisfy the enablement requirement of 35 U.S.C. § 112(a) for at least the following reasons. Example 10 of the present application demonstrates that IgG inhibits the therapeutic efficacy of anti-CD38 monoclonal antibodies, whereas administration of the IgG-degrading enzyme mutant E97D_dell8 reduces the inhibitory effect of IgG on the efficacy of the anti-CD38 antibody and enhances the antitumor activity of the anti-CD38 antibody in vivo. In addition, Examples 3, 5 and 7 also demonstrate that multiple IgG-degrading enzyme mutants recited in currently amended claim 1 exhibit better IgG-degrading activity and thermal stability compared to the wild-type. Since the therapeutic mechanism of the IgG-degrading enzymes is based on degradation of excessive IgG, mutants retaining enhanced IgG-degrading activity and improved stability are expected to maintain IgG degradation capacity under physiological conditions. Accordingly, the working examples and activity data demonstrate that the specification enables a person of ordinary skill in the art to make and use the full scope of the claims without undue experimentation, thereby satisfying the requirements of 35 U.S.C. § 112(a).
Applicants arguments have been fully considered but not found persuasive. The examiner acknowledges that these disclosures provide written description support for particular N-terminal truncation mutants and particular truncation substitution mutants encompass by amended claim 1. However, these disclosures do not resolve the entirety of the written description deficiency. Claim 1 is not directed merely to an IdeE mutant having one of the recited in terminal deletions. Claim 1 further requires an FC containing protein that is an antibody specifically recognizing CD38 and requires that the immunoglobulin degrading enzyme reduce an adverse effect of excess immunoglobulin on a therapeutic effect of the FC containing protein. Accordingly, possession must be demonstrated for the claim combination having the recited functional relationship commensurate with the scope of the claim. Applicant relies upon paragraphs 0144-0145 and example 10 as support for this relationship. However, example 10 demonstrates the asserted therapeutic effect in a limited experimental system using the particular IgG degrading enzyme E97D_del18 and an anti-CD38 monoclonal antibody. The demonstration that one particular enzyme/anti CD38 antibody combination exhibits the recited therapeutic effect does not, without additional representative disclosure or identifying characteristics, recently conveyed possession of the substantially broader genus encompassed by claim 1. In particular, claim 1 is not limited to the anti CD38 antibody employed in example 10, to antibodies having the same structure or sequence as that antibody, t0 antibodies binding the same CD38 epitope, or to antibodies operating through the same therapeutic mechanism. Rather, claim one encompasses an antibody generally that specifically recognizes CD38, provided the remaining limitations are satisfied.
The breath and functional diversity of this antibody genus are further evidenced by the dependent claims which encompass anti-CD38 antibodies having additional binding specificities including binding to CD3, CD4, CD138, IL15R, TNF alpha, a human FC receptor, and membrane or receptor bound IL-15. The specification does not provide representative working examples demonstrating the recited reduction in the adverse effect of excess immunoglobulin for these different classes of anti CD38 antibodies, nor does applicant identify a known or disclosed correlation between the structural characteristic of recognizing CD38 and the particular therapeutic response required by claim 1. Applicants assertion that the disclosed species share a common structural limitation therefore does not fully address the rejection. The N-terminal deletion may constitute a shared structural characteristic of the clean enzyme genus, but it does not establish a structural or functional characteristic identifying the claim anti CD38 antibody genus as one for which the recited therapeutic effect necessarily predictably occurs. Nor does it establish that the demonstrated interactions betweenE97D_del18, excess immunoglobulin, and the exemplified anti CD38 antibody is representative of the therapeutic relationship throughout the claimed combinations.
The applicant additionally argues that examples 3, 5, and 7 demonstrate improved IgG degrading activity and thermal stability for multiple mutants and that mutants retaining such activity would be expected to maintain IgG degradation under physiological conditions. This argument establishes a relationship between certain structural modifications of the enzyme and IgG degrading activity. The claim function, however, is not merely IgG degradation. Claim 1 requires that degradation results in a reduction of the adverse effect of excess immunoglobulin on the therapeutic effect of the FC containing anti-cd38 antibody. Applicant has not established that IgG degrading activity alone demonstrates this latter therapeutic relationship extends throughout the breadth of anti CD38 antibodies encompassed by the claim. Thus, while the amended claims and cited portions of the specification were particularly defined and support the ide truncation component of the combination, the disclosure still does not provide a representative number of species or sufficient identifying characteristics demonstrating the possession of the claimed functional combination across the breadth of the anti CD38 antibody genus.
Furthermore, Applicants arguments regarding the disclosed truncation mutants do not fully address the breadth of claim 1. The examiner acknowledges that the specification discloses mutants having deletion of the first 15-19 N terminal amino acids in particular, truncation mutants containing specified substitutions. However, claim one recites that the mutant comprises the specified deletion and does not limit the number of positions of additional substitutions or other sequence modifications. Thus, the disclosed truncation and truncation/substitution species do not necessarily represent the structural variation encompassed by claim 1. This interpretation is consistent with the dependent claim 2, which distinguishes mutants that only comprise the recited deletion from mutants containing the deletion together with substitutions at specified positions. Claim 1 contains no corresponding restriction. The specification does not establish that mutants containing additional modifications throughout SEQ ID NO:62 would retain the properties necessary to achieve the functional result required by claim 1. Accordingly, the disclosed species do not reasonably convey possession of a full mutant genus encompassed by claim 1.
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, 7-14, 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 19/194184 (reference application) in view of Crispin (US20150125443 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims a combination of an immunoglobulin degrading enzyme (IddE truncation mutants) and Fc containing protein of anti-CD38 (see claim 1); IgG cysteine protease from S. Pyogenes, in particular IdeE SEQ ID NO;62 with truncation and/or mutations (claims 2-3); wherein the enzyme is one of SEQ ID Nos:78-82 and 82-54 (truncation/substitution); further comprising a B-cell depleting agent (Claim 5); specific antibody against CD38 (Claim 7, daratumumab or isatuximab); recognizes CD38 and induces cytotoxicity (Claim 8); linked to a drug (Claim 9); binding to CD138 (Claim 10); anti-CD38 antibody sequences that encompass Daratumumab (claim 11); a carrier (claim 12); liquid (claim 13) and immobilized on a surface (claim 14) and kit thereof (claim 20).
Copending Application No. 19/194184 claims a method of administering immunoglobulin degrading enzyme IdeE in combination with an Fc containing protein, a truncation of up to 19 amino acids of SEQ ID NO:2 which is instant SEQ ID NO:62 (see claims 1, 5-6);substitutions at one or more positions of 24, 59, 280 (the same as the instant claims); mutants comprising SEQ ID Nos:3-36 which overlap with the instant claimed mutants (see claim 4, SEQ ID NO:18 I the same as instant SEQ ID NO:78); an additional B-cell depleting agent (claim 11); CD38 antibody (Claim 12); Daratumumab (claim 13); Fc fused to a drug (claim 16).
Copending Application No. 19/194184 is silent to the enzyme being immobilized on a surface. Crispin teaches wherein the Immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine protease produced by the human pathogen S. pyogenes (see paragraph 0108). Crispin teaches that the combination is a composition comprising the agent which reduces Fc receptor binding of endogenous serum antibodies (i.e. IdeS) and the therapeutic antibody, preferably a therapeutic antibody which is resistant to the agent, as a combined preparation for simultaneous, separate or sequential use as medicament or use in therapy (see paragraph 0026). Crispin teaches wherein the formulation comprises a pharmaceutically acceptable carrier or diluent (see paragraph 0142). Crispin teaches wherein the formulation is in liquid form for administering (see paragraph 0142).
Crispin additionally teaches use of the combination via extracorporeal treatment of blood (see Example 4, paragraph 0174). Crispin teaches passing blood from the cancer patient through an Endo S column and then treating with the antibody. The Example does not show using IdeS specifically as the enzyme. However, it would have been obvious to utilize the IdeS enzyme of Crispin immobilized on the surface column of Crispin because both EndoS and IdeS are known IgG degrading enzymes taught by Crispin to reduced endogenous serum IgG levels, and substitution of one known enzyme for another to achieve the same predictable results would have been obvious to one of ordinary skill in the art.
It would have been obvious before the effective filing date of the claimed invention to perform the method of the copending application 19/194184 using extracorporeal blood treatment because Crispin teaches passing blood through an EndoS column to reduce endogenous IgG levels prior to antibody therapy (Example 4, paragraph 0174). One of ordinary skill in the art would have been motivated to apply the known extracorporeal IgG-reduction technique in the copending method to achieve the predictable result of lowering circulating IgG and improving therapeutic antibody efficacy, with a reasonable expectation of success based on the known function of IgG degrading enzymes.
Regarding the functional limitation/effect now claimed in instant claim 1 (the enzyme reduces an adverse effect…), the composition taught by copending application 19/194184 with both the IdeE enzyme and the anti-CD38 would have resulted in a composition that would have inherently led to this functional result
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants argue that Claims 1-19 of Application No. 19/194,184 are directed to a method of treating an autoantibody-mediated disorder by administering an IdeE mutant, which are patentably distinct from the present claims remain as discussed below. First, the claims of Application No. 19/194,184 are directed to a method of treatment, whereas the present claims are directed to a pharmaceutical combination defined by both its components and its functional characteristics. Second, the present claims require that the immunoglobulin degrading enzyme reduces an adverse effect of excess immunoglobulin on the therapeutic effect of the Fc-containing protein. This is an affirmative claim limitation defining the functional relationship between the two active components of the claimed pharmaceutical combination. However, the claims of Application No. 19/194,184 do not have this functional limitation. Accordingly, the present claims are patentably distinct from the claims of Application No. 19/194,184.
Applicants arguments have been fully considered but not found persuasive. The fact that the claims of the compelling application are directed to a method of treatment whereas the present claims claim a pharmaceutical combination does not by itself establish patentable distinctness for purpose of non-statutory obvious type double patenting. Applicant further argues that the claims require the immunoglobulin degrading enzyme to reduce an adverse effect of excess immunoglobulin on the therapeutic effect of the FC containing protein. However, this functional relationship does not establish patentable distinctness where the claim combination would have been obvious from the subject matter of the reference claims and the recited function represents the expected or inherent result of employing the claim components under the recited conditions. Applicant has not established that the functional limitation imparts a patentable distinctness over the subject matter encompassed by the reference claims. Accordingly, the rejection is maintained.
Claims 1-5, 7-14, 20 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 12319942 in view of Crispin (US20150125443 A1) and Bonello (see above reference). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims a combination of an immunoglobulin degrading enzyme (IddE truncation mutants) and Fc containing protein of anti-CD38 (see claim 1); IgG cysteine protease from S. Pyogenes, in particular IdeE SEQ ID NO;62 with truncation and/or mutations (claims 2-3); wherein the enzyme is one of SEQ ID Nos:78-82 and 82-54 (truncation/substitution); further comprising a B-cell depleting agent (Claim 5); specific antibody against CD38 (Claim 7, daratumumab or isatuximab); recognizes CD38 and induces cytotoxicity (Claim 8); linked to a drug (Claim 9); binding to CD138 (Claim 10); anti-CD38 antibody sequences that encompass Daratumumab (claim 11); a carrier (claim 12); liquid (claim 13) and immobilized on a surface (claim 14) and kit thereof (claim 20).
U.S. Patent No. 12319942 claims a composition comprising mutant IdeE and an antibody (claims 1 and 4). U.S. Patent No. 12319942 further claims a pharmaceutically acceptable carrier (claim 3); further comprising a drug (Claim 9); a kit thereof (claim 13); truncation of 15-19 amino acids of the N-terminus of SEQ ID NO:2 which results in the same mutants of the instant claims. U.S. Patent No. 12319942 is silent to the antibody being anti-CD38 (Daratumumab); immobilized on a surface; linked to a drug; a liquid. The intended use of US Patent No. ‘942 is treating disorders including cancer (see section 4.2).
However, Crispin teaches a pharmaceutical combination comprising a therapeutic antibody (Fc containing protein) and an agent which reduces Fc receptor binding of endogenous serum antibodies, immunoglobulin degrading enzyme for treating cancer (see claims 21, 26, 28 and 30). Crispin teaches a kit comprising the antibody and degrading enzyme (see claim 32, see paragraph 0048). Crispin teaches wherein the Immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine protease produced by the human pathogen S. pyogenes (see paragraph 0108). Crispin teaches that the combination is a composition comprising the agent which reduces Fc receptor binding of endogenous serum antibodies (i.e. IdeS) and the therapeutic antibody, preferably a therapeutic antibody which is resistant to the agent, as a combined preparation for simultaneous, separate or sequential use as medicament or use in therapy (see paragraph 0026). Crispin teaches wherein the formulation comprises a pharmaceutically acceptable carrier or diluent (see paragraph 0142). Crispin teaches wherein the formulation is in liquid form for administering (see paragraph 0142).
Crispin additionally teaches use of the combination via extracorporeal treatment of blood (see Example 4, paragraph 0174). Crispin teaches passing blood from the cancer patient through an Endo S column and then treating with the antibody. The Example does not show using IdeS specifically as the enzyme. It would have been obvious before the effective filing date to combine the teachings of Crispin with US Patent No. ‘443 in a method of treating cancer because Crispin teaches that reducing IgG with an immunoglobulin degrading enzyme improves therapeutic antibody efficacy in therapeutic treatment in including cancer. One of ordinary skill in the art would have been motivated to use the enzyme antibody compositions of Crispin to achieve predictable result of enhanced antibody therapy with a reasonable expectation of success given both references use IgG degrading enzymes together with therapeutic antibodies for the same purpose.
Furthermore, It would have been obvious before the effective filing date of the claimed invention to perform the method of US Patent NO. ‘942 using extracorporeal blood treatment because Crispin teaches passing blood through an EndoS column to reduce endogenous IgG levels prior to antibody therapy (Example 4, paragraph 0174). One of ordinary skill in the art would have been motivated to apply the known extracorporeal IgG-reduction technique in the copending method to achieve the predictable result of lowering circulating IgG and improving therapeutic antibody efficacy, with a reasonable expectation of success based on the known function of IgG degrading enzymes.
Additionally, Bonello teaches that antibodies targeting CD38 are changing the treatment strategy for multiple myeloma (see Abstract). Bonello teaches that Daratumumab is the first anti-CD38 mAb showing high efficacy and favorable toxicity profile in clinical trials as monotherapy and in combinations with the currently approved standard regimens for myeloma treatment (see page 1210, article highlights). Bonello teaches that Daratumumab works through complement dependent toxicity (see section 5.1). Bonello additionally teaches use of Daratumumab in combination with an immunomodulatory agent (see page 1212, left column, lines 5-6, right column, second paragraph). Bonello teaches “The clinical success of naked mAbs targeting CD38 prompted the preclinical development of conjugated and bispecific antibodies. Different immunotoxins and radioimmunotherapeutic agents conjugated to anti-CD38 mAbs were tested and demonstrated efficacy in preclinical models (see section 5.4). Bonello teaches of Anti-CD38 antibodies conjugated to ricin molecule and that it was effective at killing CD38 positive multiple myeloma cells (see page 1216, left column). Bonello teaches that GBR1342 is a bispecific antibody targeting CD3 and CD38 that, in preclinical studies, efficaciously redirected T cells cytotoxicity toward myeloma cells both in vitro and in mice xenograft models. Bonello teaches “Another interesting anti-CD38/anti-CD3 bispecific mAb has been developed and preclinically tested” (see page 1216, left column, last paragraph).
It would have been obvious before the effective filing date of the claimed invention to select the anti-CD38 antibody daratumumab for use in the pharmaceutical combination of US Patent No. ‘942 and Crispin. One of ordinary skill in the art would have been motivated to do so because Bonello teaches that daratumumab is a clinically effective anti-CD38 monoclonal antibody for treatment of multiple myeloma with favorable efficacy and toxicity profiles, including use in combination therapies, while Crispin teaches combining therapeutic antibodies with IgG degrading enzymes to reduce endogenous IgG interference and improve therapeutic antibody efficacy.
There is a reasonable expectation of success because Bonello teaches that daratumumab effectively targets CD38-expressing multiple myeloma cells through known antibody mediated mechanisms, including CDC, and US Patent NO. 942 encompasses therapeutic methods aimed at reducing IgG in blood prior to antibody treatment.
Furthermore, it would have been obvious before the effective filing date of the claimed invention to utilize anti-CD38 antibodies linked to cytotoxic agents, radioisotopes, drugs or additional targeting moieties. One of ordinary skill in the art would have been motivated to do so because Bonello expressly teaches conjugated and bispecific anti-CD38 antibodies, including immunotoxins, radioimmunotherapeutic agents, and anti-CD38/anti-CD3 bispecific antibodies, as effective approaches for targeting multiple myeloma cells.
There is a reasonable expectation of success because Bonello teaches that such conjugated and bispecific anti CD38 antibodies demonstrated efficacy in preclinical models, thereby evidencing that modification of anti-CD38 antibodies with cytotoxic agents or additional targeting agents represented known and predictable approaches for enhancing anti-tumor activity. Regarding the functional limitation/effect now claimed in instant claim 1 (the enzyme reduces an adverse effect…), the combination of US Patent No. ‘942, Crispin and Bonello would have resulted in a composition that would have inherently led to this functional result
Response to Applicant’s Arguments
Applicants argue that “Independent claim 1 of U.S. Patent No. 12,319,942 is directed solely to an engineered IdeE mutant. By contrast, present claim 1 is directed to a pharmaceutical combination comprising an immunoglobulin degrading enzyme and an anti-CD38 antibody; wherein the pharmaceutical combination is for use in the preparation of a medicament for treating hyperglobulinemia; and wherein the immunoglobulin degrading enzyme reduces an adverse effect of excess immunoglobulin on the therapeutic effect of the anti-CD38 antibody. Accordingly, the present claims are directed to a specific therapeutic combination characterized by a cooperative therapeutic interaction between the IdeE mutant and the anti-CD38 antibody, rather than merely the engineered IdeE mutant itself. The present claims therefore define a patentably distinct invention. Additionally, as discussed below, U.S. Patent No. 12,319,942 is a later-filed application and will expire later than the instant application, and the allowance of the present application would not result in any improper extension of patent term relative to U.S. Patent No. 12,319,942.
Applicants arguments have been fully considered but not found persuasive. Although US Patent No. ‘942 claims an engineered IdeE mutant, the rejection is not based upon the ‘942 patents claims alone, but on those claims in view of Crispin and Bonello. As set forth in the rejection, Crispin provides the Fc containing/anti-CD38 antibody teachings and the motivation for the claimed combination. Thus, Applicant’s argument that the ‘942 patent claims only the IdeE mutant does not address the combined teachings forming the basis of the nonstatutory double patenting rejection.
Applicant further argues that the presently recited functional relationship renders the claims patentably distinct. This argument is not persuasive because the combination of US Patent No. ‘942, Crispin and Bonello would have resulted in a composition that would have inherently led to this functional result. As stated above, It would have been obvious before the effective filing date of the claimed invention to select the anti-CD38 antibody daratumumab for use in the pharmaceutical combination of US Patent No. ‘942 and Crispin. One of ordinary skill in the art would have been motivated to do so because Bonello teaches that daratumumab is a clinically effective anti-CD38 monoclonal antibody for treatment of multiple myeloma with favorable efficacy and toxicity profiles, including use in combination therapies, while Crispin teaches combining therapeutic antibodies with IgG degrading enzymes to reduce endogenous IgG interference and improve therapeutic antibody efficacy. Accordingly, the recited functional relationship does not render the claimed combination patentably distinct from the subject matter of the ‘942 patent claims in view of Crispin and Bonello.
Applicants arguments regarding concerning filing and expiration dates is likewise not persuasive. Non-statutory double patenting is directed to preventing unjustified extension of exclusivity and multiple patents claiming patentability indistinct subject matter, and the applicability of the doctrine is not determined merely by which related application was filed for which patent is expected to expire later. Accordingly the rejection is maintained.
Claims 1-5, 7-14, 20 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 10, 13-18 of Co-pending 18/001876 in view of Crispin (US20150125443 A1) and Bonello (cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims a combination of an immunoglobulin degrading enzyme (IddE truncation mutants) and Fc containing protein of anti-CD38 (see claim 1); IgG cysteine protease from S. Pyogenes, in particular IdeE SEQ ID NO;62 with truncation and/or mutations (claims 2-3); wherein the enzyme is one of SEQ ID Nos:78-82 and 82-54 (truncation/substitution); further comprising a B-cell depleting agent (Claim 5); specific antibody against CD38 (Claim 7, daratumumab or isatuximab); recognizes CD38 and induces cytotoxicity (Claim 8); linked to a drug (Claim 9); binding to CD138 (Claim 10); anti-CD38 antibody sequences that encompass Daratumumab (claim 11); a carrier (claim 12); liquid (claim 13) and immobilized on a surface (claim 14) and kit thereof (claim 20).
Co-pending 18/001876 claims a mutant IdeE (immunoglobulin degrading enzyme IdeE) and in particular truncation of 15-19 amino acid from the N-terminus of IdeE SEQ ID NO:2 which overlaps with the instant claims and SEQ ID NOs (Claim1); a carrier (claim 10); an antibody Fc-containing protein (Claim 13); IdeE reduces IgG in blood (Claim 16); a kit thereof (claims 17-18) and a drug (claims 17-18). Co-pending 18/001876 is silent to the antibody being anti-CD38 (Daratumumab); immobilized on a surface; linked to a drug; a liquid. The intended use of US Copending 18/001876 is treating disorders via reducing IgG in the blood prior to antibody treatment (see Background section).
Crispin teaches a pharmaceutical combination comprising a therapeutic antibody (Fc containing protein) and an agent which reduces Fc receptor binding of endogenous serum antibodies, immunoglobulin degrading enzyme for treating cancer (see claims 21, 26, 28 and 30). Crispin teaches a kit comprising the antibody and degrading enzyme (see claim 32, see paragraph 0048). Crispin teaches wherein the Immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine protease produced by the human pathogen S. pyogenes (see paragraph 0108). Crispin teaches that the combination is a composition comprising the agent which reduces Fc receptor binding of endogenous serum antibodies (i.e. IdeS) and the therapeutic antibody, preferably a therapeutic antibody which is resistant to the agent, as a combined preparation for simultaneous, separate or sequential use as medicament or use in therapy (see paragraph 0026). Crispin teaches wherein the formulation comprises a pharmaceutically acceptable carrier or diluent (see paragraph 0142). Crispin teaches wherein the formulation is in liquid form for administering (see paragraph 0142).
Crispin additionally teaches use of the combination via extracorporeal treatment of blood (see Example 4, paragraph 0174). Crispin teaches passing blood from the cancer patient through an Endo S column and then treating with the antibody. The Example does not show using IdeS specifically as the enzyme. It would have been obvious before the effective filing date to combine the teachings of Crispin with Co-pending 18/001876 in a method of treating cancer because Crispin teaches that reducing IgG with an immunoglobulin degrading enzyme improves therapeutic antibody efficacy in therapeutic treatment in including cancer. One of ordinary skill in the art would have been motivated to use the enzyme antibody compositions of Crispin to achieve predictable result of enhanced antibody therapy with a reasonable expectation of success given both references use IgG degrading enzymes together with therapeutic antibodies for the same purpose.
Furthermore, It would have been obvious before the effective filing date of the claimed invention to perform the method of Co-pending 18/001876 using extracorporeal blood treatment because Crispin teaches passing blood through an EndoS column to reduce endogenous IgG levels prior to antibody therapy (Example 4, paragraph 0174). One of ordinary skill in the art would have been motivated to apply the known extracorporeal IgG-reduction technique in the copending method to achieve the predictable result of lowering circulating IgG and improving therapeutic antibody efficacy, with a reasonable expectation of success based on the known function of IgG degrading enzymes.
Additionally, Bonello teaches that antibodies targeting CD38 are changing the treatment strategy for multiple myeloma (see Abstract). Bonello teaches that Daratumumab is the first anti-CD38 mAb showing high efficacy and favorable toxicity profile in clinical trials as monotherapy and in combinations with the currently approved standard regimens for myeloma treatment (see page 1210, article highlights). Bonello teaches that Daratumumab works through complement dependent toxicity (see section 5.1). Bonello additionally teaches use of Daratumumab in combination with an immunomodulatory agent (see page 1212, left column, lines 5-6, right column, second paragraph). Bonello teaches “The clinical success of naked mAbs targeting CD38 prompted the preclinical development of conjugated and bispecific antibodies. Different immunotoxins and radioimmunotherapeutic agents conjugated to anti-CD38 mAbs were tested and demonstrated efficacy in preclinical models (see section 5.4). Bonello teaches of Anti-CD38 antibodies conjugated to ricin molecule and that it was effective at killing CD38 positive multiple myeloma cells (see page 1216, left column). Bonello teaches that GBR1342 is a bispecific antibody targeting CD3 and CD38 that, in preclinical studies, efficaciously redirected T cells cytotoxicity toward myeloma cells both in vitro and in mice xenograft models. Bonello teaches “Another interesting anti-CD38/anti-CD3 bispecific mAb has been developed and preclinically tested” (see page 1216, left column, last paragraph).
It would have been obvious before the effective filing date of the claimed invention to select the anti-CD38 antibody daratumumab for use in the pharmaceutical combination of Co-pending 18/001876 and Crispin for reducing IgG and treating cancer. One of ordinary skill in the art would have been motivated to do so because Bonello teaches that daratumumab is a clinically effective anti-CD38 monoclonal antibody for treatment of multiple myeloma with favorable efficacy and toxicity profiles, including use in combination therapies, while Crispin teaches combining therapeutic antibodies with IgG degrading enzymes to reduce endogenous IgG interference and improve therapeutic antibody efficacy.
There is a reasonable expectation of success because Bonello teaches that daratumumab effectively targets CD38-expressing multiple myeloma cells through known antibody mediated mechanisms, including CDC, and Co-pending 18/001876 encompasses therapeutic methods aimed at reducing IgG in blood prior to antibody treatment.
Furthermore, it would have been obvious before the effective filing date of the claimed invention to utilize anti-CD38 antibodies linked to cytotoxic agents, radioisotopes, drugs or additional targeting moieties. One of ordinary skill in the art would have been motivated to do so because Bonello expressly teaches conjugated and bispecific anti-CD38 antibodies, including immunotoxins, radioimmunotherapeutic agents, and anti-CD38/anti-CD3 bispecific antibodies, as effective approaches for targeting multiple myeloma cells.
There is a reasonable expectation of success because Bonello teaches that such conjugated and bispecific anti CD38 antibodies demonstrated efficacy in preclinical models, thereby evidencing that modification of anti-CD38 antibodies with cytotoxic agents or additional targeting agents represented known and predictable approaches for enhancing anti-tumor activity.
Regarding the functional limitation/effect now claimed in instant claim 1 (the enzyme reduces an adverse effect…), the combination of Copending AN 18/001876, Crispin and Bonello would have resulted in a composition that would have inherently led to this functional result
Response to Applicant’s Arguments
Applicant argues that the claims of U.S. Application No. 18/001,876 are directed to engineered IdeE mutants having N-terminal truncations and optional amino acid substitutions exhibiting improved activity and/or thermal stability. By contrast, the present claims are directed to a pharmaceutical combination comprising an immunoglobulin degrading enzyme and an anti-CD38 antibody for use in the preparation of a medicament for treating hyperglobulinemia. Furthermore, the present claims expressly require that the immunoglobulin degrading enzyme reduces an adverse effect of excess immunoglobulin on the therapeutic effect of the anti-CD38 antibody. Accordingly, the claims of U.S. Application No. 18/001,876 neither recite nor require: (i) a pharmaceutical combination comprising an IdeE mutant and an anti-CD38 antibody; (ii) treatment of hyperglobulinemia using such pharmaceutical combination; or (iii) the functional limitation that the immunoglobulin degrading enzyme reduces an adverse effect of excess immunoglobulin on the therapeutic effect of the anti-CD38 antibody. Therefore, the pending claims are directed to a different therapeutic combination and define a patentably distinct invention from the claims of U.S. Application No. 18/001,876. Thus, Applicant respectfully requests withdrawal of the rejection.
Applicants arguments have been fully considered but not found persuasive. Applicant argues that the claims of the co pending application are directed to engineered IdeE mutants and do not themselves recite the presently claimed pharmaceutical combination, treating hyperglobulinemia, or functional relationship between the enzyme mutant and the antibody. However, the provisional non statutory double patenting rejection is not based on the claims of the copending application alone but on those claims in view of Crispin and Bonello. As set forth in the rejection, the secondary references provide the teachings concerning the anti-CD38 therapeutic component and its use in the claim therapeutic context. Further, the recited functional limitation does not establish patentable distinctness where the combination suggested by the reference claims insider references would reasonably result in the recited reduction of the adverse effect of excess immunoglobulin on anti CD38 therapeutic activity. Regarding the functional limitation/effect now claimed in instant claim 1 (the enzyme reduces an adverse effect…), the combination of Copending AN 18/001876, Crispin and Bonello would have resulted in a composition that would have inherently led to this functional result. Accordingly, the rejection is maintained.
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 2-3 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.
Claims 2-3 recite the limitation “wherein the mutant only comprises a deletion of the first 15, 16…. N-terminal amino acids of SEQ ID NO:62…” this limitation renders claims 2-3 unclear. It is unclear whether “only comprises” requires the mutant to contain slowly the recited n-terminal deletion and excludes all additional amino acid substitutions, deletions, or other modifications, or whether “only” merely distinguishes this alternative from the subsequently recited embodiment containing substitutions at positions 24, 59, 97, or 280 while permitting other sequence modifications. Accordingly the meets and bounds of the claimed mutant cannot be determined with reasonable clarity. A suggested amendment to clarify the “only” if Applicants are wanting truncation only mutants (no substitutions) could be “wherein the mutant differs from the wild type IdeE set forth in SEQ ID NO:62 only by deletion of the first 15, 16, 17, 18 or 19 N-terminal amino acids”.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
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