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
Response to Election/Restriction filed on March 25, 2026 is acknowledged. Claims 2-3, 11, 15 were amended and claims 1-20 are pending in the instant application.
Election/Restrictions
Applicant elected without traverse Group 1 (claims 1-14, 20) drawn to a composition and without traverse SEQ ID NO:78 from List I, Fc containing protein as an antibody that binds CD38 from List II and immunosuppressant from list III in the reply filed March 25, 2026.
The restriction is deemed proper and is made FINAL in this office action. Claims 6, 15-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.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.
Claim Objection
Claim 8 claims “comprising an antibody that specifically recognizes CD38”. Claims 9-11, dependent on claim 8 claim “wherein the anti-CD38 antibody…”. It is clear that an antibody that recognizes CD38 is considered an anti-CD38 antibody, however, applicant should be consistent in terminology. It is suggested that claim 8 be amended to “antibody that specifically recognizes CD38(anti-CD38 antibody” or simply state “comprising an anti-CD38 antibody…”
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5, 7-8, 11-13 and 20 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, Claims 1-5, 7-8, 11-13, 20 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below and is based on MPEP2106.03-MPEP2106.05.
Claim Interpretation
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.”
Claims 2-3 further define the immunoglobulin degrading enzyme as naturally occurring IgG cysteine proteases derived from Streptococcus pyogenes or variants thereof, including IdeS enzymes and sequences corresponding to SEQ ID Nos1-42, 59-60, 61-95.. Claims 4-5, 7-8 further define the Fc-containing protein as antibodies and antibody fragments, including naturally occurring antibodies such as anti-CD38 antibodies. Claims 12-13 recite pharmaceutical compositions thereof and claim 14 recites immobilization of the enzyme on a surface. Claim 20 recites a kit comprising said pharmaceutical combination. Instant SEQ ID NO:78 is a naturally occurring IgG endopeptidase (see Uniprot protein accession C0M8U6_STRE4, see attached handout).
Subject Matter Eligibility Test for Products and Processes
Step 1: Is the claim to a process, machine, manufacture, or composition of matter? (see MPEP 2106.03)
Yes, the instant claims are directed to statutory categories including compositions of matter.
Step 2A(1): Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea? (see MPEP 2106.04)
Yes, the claims are directed to a natural phenomenon, namely naturally occurring immunoglobulin degrading enzymes and naturally occurring Fc-containing proteins such as antibodies and immunoglobulins.
The specification describes immunoglobulin degrading enzymes derived from Streptococcus pyogenes, including IdeS enzymes, which are naturally occurring bacterial cysteine proteases capable of cleaving IgG. The specification further describes Fc-containing proteins including antibodies and immunoglobulins, which are naturally occurring proteins.
Accordingly, the pending claims are directed to naturally occurring proteins and combinations thereof. As the claimed products are found in nature, consideration is given to whether the claims integrate the judicial exception into a practical application or contain additional elements that provide a marked difference as compared to the natural counterparts.
Step 2A(2): Does the claim recite additional elements that integrate the judicial exception into a practical application? (see MPEP 2106.04(d))
No. The judicial exception is not integrated into a practical application.
The claims merely recite combining naturally occurring proteins together in a pharmaceutical combination or composition. The claims do not require any structural modification to the naturally occurring proteins that results in a marked difference in structure or function from the naturally occurring counterparts.
Regarding claim 1, the limitation “for use in the preparation of a medicament for treating hyperglobulinemia” is interpreted as an intended use and does not affirmatively recite a treatment step. Intended use language does not impose a meaningful limit on the claimed composition itself and does not alter the structure or physical characteristics of the naturally occurring proteins.
Similarly, claims 12-14 merely recite pharmaceutical compositions, carriers, diluents, lyophilized powders, liquids, or immobilization on a surface. Such additional elements are well-understood, routine, and conventional activities in the pharmaceutical arts and do not integrate the judicial exception into a practical application. Furthermore, given the broadest reasonable interpretation, a carrier could be naturally occurring water which does result in a marked difference in structure or function.
Regarding claims 15-16, the administration of naturally occurring proteins for their naturally occurring function of IgG degradation and antibody binding merely applies the natural properties of the claimed products and does not recite additional elements sufficient to integrate the exception into a practical application.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception? (see MPEP 2106.05)
No, the claims do not recite additional elements that amount to significantly more than the judicial exception.
The claims are directed to combinations of naturally occurring proteins performing their naturally occurring functions. The immunoglobulin degrading enzyme performs its natural IgG-cleaving activity, while the Fc-containing protein performs its natural antibody binding function. There is no evidence in the specification that the claimed combination results in a markedly different characteristic from the naturally occurring counterparts.
The recited pharmaceutical formulations, carriers, diluents, lyophilized powders, liquids, immobilized surfaces, and administration steps are conventional and routine in the pharmaceutical arts. Merely combining naturally occurring products with conventional pharmaceutical components does not amount to significantly more than the judicial exception.
Further, the recited treatment of hyperglobulinemia and related diseases constitutes an intended result of administering the naturally occurring products and does not impart a structural or functional difference to the claimed compositions themselves.
In sum, when the relevant considerations are analyzed, they weigh against a finding of significantly more than the judicial exception. Accordingly, claims 1-5, 7-8, 11-13 and 20 do not qualify as eligible subject matter under 35 U.S.C. 101.
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.
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.” The scope of claim 1 is extremely broad and encompasses any immunoglobulin degrading enzyme, any FC-containing protein, pharmaceutical combinations thereof and treatment of hyperglobulinemia generally. Dependent claims further broaden the scope by encompassing IgG cysteine proteases derived from S. pyogenes, human derived MMP proteases and variants thereof, variants possessing IgG digesting activity, enzymes comprising SEQ ID Nos:1-42, 59-95, antibodies, IgGs, immunoadhesions, therapeutic agents, diagnostic agents, imaging agents, and antibody drug conjugates as Fc proteins, and combinations further comprising chemo agents, hormone agents, proteasome inhibitors, B cell depleting agents, targeted preparations and immunosuppressants. Additionally, the claims are directed not merely to IgG cleavage activity, but to the therapeutic use of treating hyperglobulinemia. Thus, the claims encompass a very large functional genus or enzyme/protein combinations and desired therapeutic effects extending substantially beyond the exemplified embodiments.
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 pre existing 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.
Importantly, the specification does not provide actual reduction to practice demonstrating treatment of hyperglobulinemia broadly. The examples do no demonstrate the desired therapeutic effects across the broad range of claimed enzyme and Fc-containing protein combinations or any sort of structure function correlation. Accordingly, the specification demonstrates reduction to practice only for a relatively small number of specifically disclosed enzyme constructs and experimental systems.
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.
The specification does not provide sufficient identifying characteristics to demonstrate possession of the full claimed genus. While the specification discloses certain specific sequences and mutations, the claims broadly encompass immunoglobulin degrading enzymes generally, variants thereof, broad classes of Fc containing proteins and treatment of hyperglobulinemia.
The specification does not disclose a representative number of species spanning the full scope of the claimed genus, common structural motifs predictive of claimed function across the full scope, conserved residues required for activity across the claimed genus, structural limitations defining which variants fall with the invention or sufficient guidance identifying which modifications would maintain the claimed properties and therapeutic utility.
The disclosure instead relies predominantly upon function language such as IgG digesting activity, enhanced cleavage, improved thermal stability, reduced immunogenicity, enhancement of antibody therapy and therapeutic use for hyperglobulinemia. However, the functional language alone is insufficient to demonstrate possession of a broad genus in an unpredictable art absent sufficient representative species or an established structure function correlation.
Physical/Chemical Properties
Although the specification provides certain experimental data relating to cleavage activity, thermal stability, serum plasma cleavage and antibody recognition, such data is limited to a relatively small subset of disclosed mutants, particularly E97D_del18 and related constructs. The specification does not provide sufficient physical or chemical characterization across the full breadth of immunoglobulin degrading enzymes, variants thereof, Fc containing proteins or therapeutic combinations encompassed by the claim. Applicants specification lacks substrate specificity across the claimed genus, sequence conservation requirements, stability requirements, immunogenicity profile or therapeutic requirements. The specification does not characterize the broad range of Fc-containing proteins encompassed by the claims beyond a few specific examples.
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 pre existing 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, broad classes of Fc-containing proteins, 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
The specification does not reasonably convey to one of ordinary skill in the art that applicant had possession, at the time of filing, of the full scope of the claimed invention. The disclosure is limited primarily to a relatively small number of specifically exemplified IdeE/IdeS-related mutants and limited Fc-containing protein systems, while the claims broadly encompass immunoglobulin degrading enzymes generally, variants thereof, broad classes of Fc-containing proteins, and treatment of hyperglobulinemia. The specification fails to disclose a representative number of species commensurate in scope with the claims, sufficient identifying structural characteristics, sufficient physical or chemical characterization across the full scope, sufficient support for treatment of hyperglobulinemia, or an adequate correlation between structure and function sufficient to support the broad functional genus recited.
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 and 11 is 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.
In Claim 2, the phrase “wherein the variants have at least IgG digesting activity” is unclear because it is ambiguous whether “the variants” refers to variants of the IgG cysteine protease derived from S. Pyogenes, variants of the human derived MMP protease or variants of both. Therefore, the scope of the claim cannot be reasonably determined.
Claim 11 recites, in part “…and an epitope binding fragment is involved” is indefinite because it is unclear what is meant by “involved” and how the recited epitope binding fragment relates to the previously recited anti-CD38 antibody. Specifically, it is unclear whether the anti-CD38 antibody itself is required to be one of the recited fragments, the pharmaceutical combination separately comprises such fragment, or the fragment is merely optionally present. Additionally, the claim first recites that “the anti CD38 antibody comprises at least one heavy chain and at least one light chain”, but subsequently recites fragments including scFv and disulfide-linked Fv fragments, which do not necessarily comprise both a heavy chain and a light chain as separately recited. Therefore, it is unclear whether the claim requires a full length antibody, an antibody fragment or both. Accordingly, the metes and bounds of claim 11 cannot be determined with reasonable certainty.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 4, 12-13 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Crispin (US20150125443 A1).
Claim interpretation: the claimed pharmaceutical combination is interpreted as requiring both an immunoglobulin degrading enzyme and an Fc-containing protein for combined therapeutic use, wherein the components may be administered or formulated simultaneously, separately or sequentially (see specification, paragraph 0044).
Regarding claims 1 and 4, 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, (see claims 21, 26, 28 and 30). Regarding claim 20, Crispin teaches a kit comprising the antibody and degrading enzyme (see claim 32, see paragraph 0048). Regarding claim 2, Crispin teaches wherein the Immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine protease produced by the human pathogen S. pyogenes (see paragraph 0108). Regarding claim 12, 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). Regarding claim 13, Crispin teaches wherein the formulation is in liquid form for administering (see paragraph 0142).
Claim Rejections - 35 USC § 103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 4, 12-14, 20 are rejected under 35 U.S.C. 103 as being unpatentable over Crispin (US20150125443 A1).
Claim interpretation: the claimed pharmaceutical combination is interpreted as requiring both an immunoglobulin degrading enzyme and an Fc-containing protein for combined therapeutic use, wherein the components may be administered or formulated simultaneously, separately or sequentially (see specification, paragraph 0044).
Regarding claims 1 and 4, 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, (see claims 21, 26, 28 and 30). Regarding claim 20, Crispin teaches a kit comprising the antibody and degrading enzyme (see claim 32, see paragraph 0048). Regarding claim 2, Crispin teaches wherein the Immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine protease produced by the human pathogen S. pyogenes (see paragraph 0108). Regarding claim 12, 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). Regarding claim 13, Crispin teaches wherein the formulation is in liquid form for administering (see paragraph 0142).
Crispin is silent to the immunoglobulin degrading enzyme (IdeS) is immobilized on a surface.
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 before the effective filing date of the claimed invention 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.
Claim(s) 3 is rejected 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).
Claim interpretation: the claimed pharmaceutical combination is interpreted as requiring both an immunoglobulin degrading enzyme and an Fc-containing protein for combined therapeutic use, wherein the components may be administered or formulated simultaneously, separately or sequentially (see specification, paragraph 0044).
Regarding claims 1 and 4, 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, (see claims 21, 26, 28 and 30). Regarding claim 20, Crispin teaches a kit comprising the antibody and degrading enzyme (see claim 32, see paragraph 0048). Regarding claim 2, Crispin teaches wherein the Immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine protease produced by the human pathogen S. pyogenes (see paragraph 0108). Regarding claim 12, 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). Regarding claim 13, Crispin teaches wherein the formulation is in liquid form for administering (see paragraph 0142).
Crispin is silent to the sequence of the IdeS enzyme.
However, Crispin does teach “Immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine protease produced by the human pathogen S. pyogenes (von Pawel-Rammingen et al. EMBO J. 2002 Apr. 2; 21(7): 1607-1615.). IdeS catalyzes a single proteolytic cleavage in the lower hinge of human IgG (U.S. Pat. No. 7,666,582).”
Rammingen teaches “A polypeptide isolated from S. pyogenes is described, having IgG cysteine protease activity. The protease is designated IdeS, Immunoglobulin G-degrading enzyme of S. pyogenes” (see abstract). Rammingen teaches wherein the IdeS comprises instant SEQ ID NO:1 (see SEQ ID NO:2, IdeS with the putative signal sequence, see Figure 2).
It would have been obvious before the effective filing date of the claimed invention to utilize the IdeS sequence disclosed by Rammingen in the pharmaceutical combination of Crispin. One of ordinary skill in the art would have been motivated to do so because Crispin expressly teaches the use of an immunoglobulin G-degrading enzyme, including IdeS, for reducing endogenous IgG interference, while Rammingen provides the known amino acid sequence and characterization of IdeS as an IgG cleaving cysteine protease from S. pyogenes, thereby providing a recognized enzyme suitable for use in Crispin’s system with a reasonable expectation of success. There is a reasonable expectation of success because Rammingen expressly teaches that the disclosed IdeS sequence encodes a functional IgG-cleaving cysteine protease from S. pyogenes, and Crispin teaches the use of such immunoglobulin degrading enzymes for reducing endogenous IgG interference in therapeutic antibody administration, such that the references are directed to the same known function and purpose.
Claim(s) 5, 7-11 are rejected 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)..
Claim interpretation: the claimed pharmaceutical combination is interpreted as requiring both an immunoglobulin degrading enzyme and an Fc-containing protein for combined therapeutic use, wherein the components may be administered or formulated simultaneously, separately or sequentially (see specification, paragraph 0044).
Regarding claims 1 and 4, 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, (see claims 21, 26, 28 and 30). Regarding claim 20, Crispin teaches a kit comprising the antibody and degrading enzyme (see claim 32, see paragraph 0048). Regarding claim 2, Crispin teaches wherein the Immunoglobulin G-degrading enzyme (IdeS) is an extracellular cysteine protease produced by the human pathogen S. pyogenes (see paragraph 0108). Regarding claim 12, 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). Regarding claim 13, Crispin teaches wherein the formulation is in liquid form for administering (see paragraph 0142). Crispin additionally teaches treatment of multiple myeloma (see paragraph 0070 and claim 21).
Regarding claim 7-11, Crispin suggests the antibody is daratumumab (anti-CD38 antibody) in a large list of antibodies (see claim 25, paragraph 0122).
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). Regarding claim 8, Bonello teaches that Daratumumab works through complement dependent toxicity (see section 5.1). Regarding claim 5, Bonello additionally teaches use of Daratumumab in combination with an immunomodulatory agent (immunosuppressant, see page 1212, left column, lines 5-6, right column, second paragraph). Regarding claim 9, 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). Regarding claim 10, 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 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 Crispin teaches daratumumab as a therapeutic antibody and method of improvement of efficacy of therapeutic antibodies, such that the references are directed to compatible therapeutic approaching for enhancing antibody based cancer treatment.
Regarding claims 5, 9-10, 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 including immunosuppressants. 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 and or additional therapeutic drugs represented known and predictable approaches for enhancing anti-tumor activity.
Regarding claim 11, as evidenced by KEGG DRUG, Daratumumab comprises SEQ ID Nos:43-45 and 46-48 thus meeting the limitations of instant claim 11.
Regarding claim 5 and addition of another therapeutic agents such as chemotherapy or immunosuppressants, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir. 1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive....Appellant argues... hindsight reconstruction or at best,... obvious to try’.... We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known (anti-CD38 antibody in combination with known cancer treatments, chemotherapeutics, immunosuppressants) to be useful for the same purpose, with a reasonable expectation that at least here will be an additive effect.
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 and Fc containing protein (see claim 1); IgG cysteine protease from S. Pyogenes (claim 2); wherein the enzyme comprises one of SEQ ID Nos:1-42, 59-60, 61-55 (claim 3); Fc containing protein is an antibody (claim 4); further comprising a B-cell depleting agent (Claim 5); Fc containing protein is antibody against CD38 (Claim 7); recognizes CD38 and induces cytoxicity (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 (see claims 1, 5-6); 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 and IdeS (SEQ ID NO:2). 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 one 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, 7-14, 20 are 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 and Fc containing protein (see claim 1); IgG cysteine protease from S. Pyogenes (claim 2); wherein the enzyme comprises one of SEQ ID Nos:1-42, 59-60, 61-55 (claim 3); Fc containing protein is an antibody (claim 4); further comprising a B-cell depleting agent (Claim 5); Fc containing protein is antibody against CD38 (Claim 7); recognizes CD38 and induces cytoxicity (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). 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.
Claims 1-5, 7-14, 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-10, 13-18 of Co-pending 18/001876 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 and Fc containing protein (see claim 1); IgG cysteine protease from S. Pyogenes (claim 2); wherein the enzyme comprises one of SEQ ID Nos:1-42, 59-60, 61-55 (claim 3); Fc containing protein is an antibody (claim 4); further comprising a B-cell depleting agent (Claim 5); Fc containing protein is antibody against CD38 (Claim 7); recognizes CD38 and induces cytoxicity (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) (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.
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
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