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
Claim Status
Applicant’s amendment filed March 21, 2024 was received and entered.
Claims 1-13, and 15 have been amended.
Claim 14 has been canceled.
Claims 16-21 have been added.
Claims 1-13 and 15-21 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of 371 of PCT/EP2022/050704 filed January 14, 2022, which claims priority to foreign application EP 21151575.4 filed January 14, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted 3/21/2024, 6/28/2024, 12/10/2024, 4/02/2025, 6/20/2025, 12/19/2025, and 2/17/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 5-6 are objected to for the following informalities:
Claims 5-6 the term “SEQ ID NO.:”, however, it should be written as “SEQ ID NO:”.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Claim 21 limitation “means for binding human CD38” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The claim limitations have been interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because they use a non-structural limitation means for binding human CD38 protein, which couples functional language without reciting sufficient structure to achieve the function.
Therefore “means for binding human CD38” has been interpreted as any means for binding human CD38, in light of the specification for the purpose of examination.
It is noted that this is not a rejection under 35 U.S.C. 112(f).
Claim Rejections - 35 USC § 112(b)
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.
Claims 15 and 21 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 15 recites “the subject is characterized by proteinuria at screening of ≥ 1.0 g/day”. It is unclear when the “at screening” occurs. Is it the proteinuria level before treatment? Is screening over multiple days?
Claim 21 limitation “means for binding human CD38” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. The specification merely recites a function of binding CD38, but does not identify any specific structure that binds human CD38. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Written Description
Claims 1-4, 7-13, and 15-21 are rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 7-10, 13, and 16-21 recite an anti-CD38 antibody or antibody fragment.
The claims encompass a large genus of antibodies, comprised of different combinations of heavy and light chain amino acid sequences, respectively, which represent structurally distinct polypeptides. The state of the art is such that antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. As taught by Janeway et al. (2001), the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. See also Rabia et al. (2018), which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (pg. 4). The state of the art is such that antibody production is extremely complex and requires a deep understanding of protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system. The development of candidate antibodies involves a complex process of clinical and preclinical evaluation that include identification of the physical and chemical properties of the antibody (Scott et al., 2012, p. 278-279). Antibodies have a wide range of pharmacokinetics, size and immunogenicity, affinities and avidities, all of which effect the function of each antibody in vivo (p. 278). Furthermore, antibodies can have various effector functions including receptor blockage, reducing signaling, or in vivo cell depletion, and that antibody isotype alone is not predictive of in vivo function (Chan et al., 2010, p. 307).
In regard to anti-CD38 antibodies in particular, the art recognizes that the function of
CD38 binding antibodies in terms of functional outcome for immunity is extremely complex and
unpredictable. For example, van de Donk (2018) teaches that CD38 antibodies kill tumor cells via Fc-dependent immune effector mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and apoptosis upon secondary cross-linking. CD38-targeting antibodies differ with respect to their potency to induce CDC, ADCC, ADCP, or apoptosis upon secondary cross-linking due to the unique epitopes of the different CD38 antibodies (pg. 2, col. 1, par. 3).
The claims also encompass a broad genus of structurally different antibodies. For example, the claims would encompass monoclonal antibodies, or fragment thereof, derived from both human and cynomolgus monkey, that would have different VH and VL sequences. Additionally, the claims encompass a genus of antibodies that bind to different epitope regions of CD38, or those with different affinities or pharmacokinetic properties.
The specification discloses the structure (i.e., amino acid sequence) of only one anti-CD38 antibody (felzartamab). However, the specification does not disclose a correlation between the structure of the antibodies and the function of binding to CD38 broadly, or human CD38 as claimed in instant claim 21. Furthermore, the specification broadens the term “anti-CD38 antibody” by defining as any molecule that specifically binds to CD38 or inhibits the activity or function of CD38, or which by any other way exerts a therapeutic effect on CD38. The term "anti-CD38 antibody" includes, but is not limited to, antibodies specifically binding to CD38, alternative protein scaffolds binding to CD38, nucleic acids (including aptamers) specific for CD38 or small organic molecules specific for CD38 [pg. 6, lines 14-20].
The instant application has not provided a sufficient description showing possession of the
necessary 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 genus of antibodies encompassing various structures, specificities and
functions.
Given the well-known high level of polymorphism of antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of anti-C38 antibodies with the claimed specificity and functional attributes, broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus.
The Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent
specification to “describe the claimed invention so that one skilled in the art can recognize what is
claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s
“disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter
purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir.
1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with
reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession
of the invention. The invention is, for purposes of the 'written description’ inquiry, whatever is now
claimed." (See Vas-Cath, p. 1117). The specification does not "clearly allow persons of ordinary skill in
the art to recognize that [he or she] invented what is claimed." (See Vas-Cath, p. 1116).
Also, it is noted that the Court has held that the disclosure of screening assays and general
classes of compounds was not adequate to describe compounds having the desired activity: without
disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of
Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in
“possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support
need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein
v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —
i.e., what the written description and knowledge in the art would lead one to speculate as to
modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also
ensures that when a patent claims a genus by function, the specification recites sufficient materials to
accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broadly class of antibodies, in the absence of sufficient disclosure of relevant
identifying characteristics, the patentee must establish “a reasonable structure-function correlation”
either within the specification or by reference to the knowledge of one skilled in the art with functional
claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at
best describes plan for making antibodies with the “limitations above” and then identifying those that
satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient.
Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is
insufficient written description of the required kind of structure-identifying information about the
corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v.
Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that
the specification fails to provide adequate written description to demonstrate that Applicant was in
possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398. Therefore, there is insufficient written description for genus of anti-C38 antibodies in method of treatment of a subject encompassed by the claimed invention to provide sufficient structure for the anti-CD38 antibodies claimed at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Claims 2-4, 11-12, and 15 are included in the rejection because they depend from or otherwise require all the limitations of a rejected claim and fail to clarify the issue.
Enablement
Claims 1-13 and 15-21 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The instant claims are drawn to a method for the treatment of an immune complex-mediated disease comprising administering an anti-CD38 antibody or fragment.
The specification does not reasonably provide enablement for treatment any immune complex-mediated disease, including IgA nephropathy, lupus nephritis, Henoch-Schönlein purpura nephritis, post-streptococcal glomerulonephritis, or drug-induced immune complex-mediated diffuse proliferative glomerulonephritis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
The instant claims are directed to a method for the treatment of an immune complex-mediated disease in a subject, comprising administering an anti-CD38 antibody or antibody fragment, including the anti-CD38 antibody felzartamab recited in claims 5-6. The claims are broad and inclusive of all types of immune complex-mediated diseases. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad due to the vast number of possible “immune complex-mediated diseases”.
An immune complex-mediated disease is not a single disease, or cluster of closely related disorders. In fact, Chauhan (2017) teaches that immune complexes (ICs) are formed when foreign and modified self-antigens bind to natural IgM. Accumulation of abnormal immune complex levels triggers disease pathologies such as nephropathies, autoimmunity, cancers, infections, and lung injury.
The instant specification defines IC-mediated diseases as those relating to circulating ICs generated in type III immune responses [pg. 1-2].
Examples of type III hypersensitivity reactions include serum sickness, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), leukocytoclastic vasculitis, cryoglobulinemia, acute hypersensitivity pneumonitis, and several types of glomerulonephritis.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
While the state of the art is relatively high with regard to the treatment of IC-mediated disorders related to type III hypersensitivity reactions, the state of the art with regard to treating IC-mediated diseases broadly is underdeveloped. In particular, there is no known agent that is effective against all IC-mediated diseases, and treatment involves a very high level of unpredictability. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all IC-mediated diseases in a subject with the claimed anti-CD38 antibody or antibody fragment makes practicing the claimed invention unpredictable.
With regard to treatment of immune complex disease, Moreland (eds) (2004) states, therapy depends on the cause of the disease. If the source of the antigen is an infection, treatment of disease (with antiviral or antibiotic drugs) to remove the source of the antigen would alleviate the problem. Unfortunately in most cases of immune complex disease the inciting antigen is not known, which makes prevention of immune complex formation impossible. As there is no single cause of immune complex disease there is no single therapy, and so the clinical approach is to treat the symptoms of the underlying disease state (pg. 442-443).
Regarding the specific IC-mediated conditions recited in instant claim 4:
Natale et al., (2020), teaches the optimal management of IgA nephropathy remains uncertain although corticosteroid therapy may lower the risks of kidney disease progression and need for dialysis or transplantation. Evidence for treatment effects of immunosuppressive agents on death, infection, and malignancy is generally sparse or low‐quality. Steroid therapy has uncertain adverse effects due to a paucity of studies. Available studies are few, small, have high risk of bias and generally do not systematically identify treatment‐related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible due to a lack of studies. There is no evidence that other immunosuppressive agents, including cytotoxic agents, improve clinical outcomes in IgA nephropathy. (Conclusion, pg. 27).
Furthermore, the art indicates no one treatment exists for lupus nephritis, and the main goal of treatment is management of symptoms with medicines such as Lupkynis that binds and blocks calcineurin, a monoclonal antibody against B cells (Benlysta), steroids, and immunosuppressives. Treatments also include medicines or other ways to control high blood pressure, diabetes or high cholesterol (www.lupus.org/resources/how-lupus-affects-the-renal-kidney-system; 13 Jan 2021).
Additionally, Nickavar teaches there is no consensus for the treatment of Henoch Schönlein nephritis, and the most effective treatment remains controversial. It has been suggested that early corticosteroids treatment may not prevent the development of HSN and should not be routinely recommended. Early immunosuppressive therapy with high dose corticosteroids, cyclophosphamide, azathioprine, calcineurin inhibitors, mycophenolate mofetil (MMF), rituximab, mizoribine, or methotrexate have been suggested in patients with significant kidney involvement (proteinuria in nephrotic range and/or progressive kidney impairment). The main objectives of immunosuppressive treatments are prevention of irreversible glomerular fibrosis with increasing proteinuria and improvement long term renal outcome (pg. 1-2).
Moreover, Fox (2019) teaches treatment of post-streptococcal glomerulonephritis focuses primarily on symptom management. And although penicillin is often given to treat possible residual strep infection, the strep infection being treated by the antibiotic is not “in the kidneys”.
Lastly, Moledina et al. (2018) teaches acute tubulointerstitial nephritis (AIN) kidney injury is caused by infiltrating immune cells, and it is thought to be due to either an allergic reaction triggered by commonly used medications, such as antibiotics, proton pump inhibitors, and nonsteroidal anti-inflammatory drugs, or a loss of immune tolerance, such as occurs with immune checkpoint inhibitors. The current standard of care for drug-induced AIN management includes early identification of this disease and prompt discontinuation of the culprit medication. Given the underlying immune-mediated damage in drug-induced AIN, corticosteroid therapy has also been used since the 1970s. However, there is a lack of high-quality evidence to support this practice (pg. 1785, par. 1).
Given the lack of predictability in treating immune complex-mediated diseases, one of skill in the art would have to engage in undue experimentation to first identify individuals to which the instant method would apply, and to further treat patients with the instantly claimed anti-CD38 antibody.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
The instant specification discloses one anti-CD38 antibody known as felzartamab and MOR202. The instant specification does not disclose any data related to the treatment of any immune complex-mediated disease with felzartamab or any other anti-CD38 antibody. In fact, the specification merely sets forth in vitro data using anti-tetanus toxoid titers as a surrogate marker for to demonstrate a reduction in plasma cells [Fig. 1]. Also disclosed are prophetic in vivo protocols to evaluate the ability of felzartamab in the depletion of autoantibody secreting plasma cells, as well as a study protocol to test dosing and efficacy of felzartamab in the treatment of IgA nephropathy. However, no anti-CD38 antibody was ever tested in the disclosed in vitro or in vivo models to demonstrate an effect on any disease. As such, without any working examples, the application is not enabled for treating any immune complex-mediated disease. One of skill in the art would be required to engage in extensive, difficult experimentation to first develop criteria for identification of immune complex diseases, which is known to be unpredictable as indicated above, and second select and identify an anti-CD38 antibody or antibody fragment that would possess the required functionality for the specific types of immune complex-mediated diseases effecting the kidneys. This required experimentation is undue.
In conclusion, the claimed invention does not provide enablement for treatment of any immune complex-mediated disease. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 7, 10, and 17-19 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Campbell et al. (WO 2020/081881; cited IDS 3/21/2024) (“Campbell”). This reference qualifies as prior art under both 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2).
The instant claims are drawn to a method for the treatment of an immune complex-mediated disease in a subject comprising administering to the subject an anti-CD38 antibody or antibody fragment, wherein the immune complex-mediated disease is a kidney disease selected from IgA nephropathy, lupus nephritis, and those recited in instant claim 3. The anti-CD38 antibody is an IgG1 isotype and is administered in one or more doses, for at least 2 or 5 doses, at a concentration of 650 mg to 1625 mg.
Campbell discloses a method of providing treatment of an autoimmune disease in a subject in need thereof, comprising administering an anti-CD38 antibody, wherein the total dosage of the anti-CD38 antibody is about 10 mg to about 2,400 mg per administration [claim 12; instant claims 1, 19].
The autoimmune disease is selected from the group including rheumatoid arthritis, systemic lupus erythematosus (SLE) and lupus nephritis [claim 23; instant claims 2-3].
Campbell discloses the anti-CD38 antibody is an IgG1 isotype [claim 29; instant claim 7] and is administered in a single dose, or two to five doses [claims 14-15; instant claims 17-18]. Administration of the anti-CD38 antibody results in less than 80% depletion of plasma cells [claim 19; instant claim 10].
The antibody concentration recited in the instant claims (650 -1625 mg) is well within the range disclosed by Campbell. Additionally, the instant specification provides protocols to assess efficacy of the anti-CD38 antibody in the treatment of immune complex-mediated disease by measuring the reduction of plasma cells. Therefore, the less than 80% reduction in plasma cells (including up to 79% reduction) reads on the reduction of immune complexes as recited in instant claim 10. Therefore, absent a showing of any difference, the methods disclosed by the prior art are deemed to anticipate the claimed methods.
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.
Claims 1, 8-9, 13, and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (WO 2020/081881; cited IDS 3/21/2024) (“Campbell”).
The instant claims are drawn to a method for the treatment of an immune complex-mediated disease in a subject comprising administering to the subject an anti-CD38 antibody or antibody fragment, wherein the antibody is a human antibody that depletes plasma cells by binding CD38 resulting in antibody dependent cell mediated cytotoxicity (ADCC) and/or antibody dependent cellular phagocytosis (ADCP). The anti-CD38 antibody is administered according to body weight in one to five doses of about 13.0 mg/kg to 19.3 mg/kg.
The teachings of Campbell are set forth above.
In addition, Campbell specifically teaches the anti-CD38 antibody DARZALEX® (daratumumab), which is a human immunoglobulin GI kappa (IgG1k) monoclonal antibody (mAb) that binds to CD38. It is a targeted immunotherapy that depletes cells that express high levels of CD38, by a variety of mechanisms, including complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP) [0007; instant claims 1, 8-9, 21].
Campbell also teaches that in rheumatoid arthritis (RA), CD38 and plasma cell-related genes are highly expressed in the synovial tissue of RA patients at all the stages of the disease. Thus, CD38 may be targeted to selectively deplete and modify plasma cells to affect pathogenesis of RA and other autoimmune diseases [0009].
Campbell provides dosing for a therapeutically effective amount dosing for the anti-CD38 antibody based on body weight of 5 mg/kg to 25 mg/kg, wherein the dose given to the subject is sufficient to alleviate or at least partially arrest the disease being treated [00145].
Campbell teaches all the limitations of the rejected instant claims. The dosage range for the anti-CD38 antibody recited in the instant claims (13.0 mg/kg to 19.3 mg/kg) is well within the range taught by Campbell. Accordingly, the prior art of Campbell provided a prima facie case of obviousness.
Claims 4, 11-12, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (WO 2020/081881; cited IDS 3/21/2024) (“Campbell”) as applied to claims 1-3, 7-10, 13, and 17-21 above, and in further view of Selvaskandan et al. (Clin Exp Nephro (2019) 23: 577-588; cited IDS 3/21/2024) (“Selvaskandan”), as evidenced by Klunker et al. (WO 2020/187718; cited IDS 3/21/2024) (“Klunker”).
The instant claims are drawn to a method for the treatment of IgA nephropathy that is a galactose-deficient IgA1 antibody (Gd-IgA1) and anti-galactose-deficient IgA1 antibody (anti-GD-IgA1)-positive IgA nephropathy, wherein the immune complex is in the glomeruli of the kidney. Subjects are characterized as having a proteinuria level of ≥ 1 g/day.
The teachings of Campbell are set forth above. In addition to treatment of lupus nephritis, Campbell teaches an anti-CD38 antibody for the treatment of IgA nephropathy [0023].
Campbell is silent regarding the pathology of the disease, or presentation of symptoms (i.e. proteinuria levels).
Selvaskandan teaches IgA nephropathy (IgAN) is an inflammatory renal disease characterized by the deposition of IgA in the glomerular mesangium of the kidney [Introduction, par. 1; instant claim 12]. Specifically, B cell activation results in the production of gd-IgA1 resulting in the generation of auto-antibodies, which leads to the formation of immune complexes. The deposition of immune complexes in the glomerular mesangium lead to varying degrees of inflammation and fibrosis. Current therapeutic targets include modulation of B cell activity leading to a reduction in GD-IgA1 auto-antibodies and circulating immune complexes [Fig. 1 (legend); instant claim 12]. One antibody targeting CD20 receptor on B cells, rituximab, has been tested for the ability to reduce Gd-IgA1 and anti-Gd-IgA1-IgG antibody production by causing B-cell depletion, which would in turn provide renoprotection [pg. 582, col. 1, par. 2; instant claim 11]. However, a trial failed to show an effect of rituximab on Gd-IgA1/autoantibody levels or proteinuria in patients with proteinuria ≥ 1 g/day [Table 2; instant claim 15].
The teachings of Campbell differ from the present invention in that although an anti-CD38 antibody for the treatment of IgA nephropathy which depletes plasma cells is taught, the IgA nephropathy is not explicitly taught as being galactose-deficient IgA1 antibody (Gd-IgA1) and anti-galactose-deficient IgA1 antibody (anti-GD-IgA1)-positive IgA nephropathy that deposits in the glomerular region of the kidneys. Given that Selvaskandan teaches a reduction in cells that produce Gd-IgA1 and anti-Gd-IgA1-IgG antibodies is a major strategy in the treatment of IgAN, artisans would be motivated to target these cell populations. One would have a reasonable expectation of success in selecting CD38 as a target for treating IgAN because CD38 is highly expressed on plasma cells in many autoimmune disorders, including membranous nephritis as evidenced by Klunker [pg. 10, lines 8-21], leading to accumulation of immune complexes. Therefore, when antibodies specific to the CD38 protein are administered to a patient, the antibody bound to CD38 leads to the destruction and depletion of cells that produce the antibodies involved in IgAN, thus providing motivation for use of an anti-CD38 antibody in the treatment of galactose-deficient IgA1 antibody (Gd-IgA1) and anti-galactose-deficient IgA1 antibody (anti-GD-IgA1)-positive IgA nephropathy. Accordingly, the combination of prior art references provided a prima facie case of obviousness.
Claims 5-6 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (WO 2020/081881; cited IDS 3/21/2024) (“Campbell”) as applied to claims 1-3, 7-10, 13, and 17-21 above, and in further view of Klunker et al. (WO 2020/187718; cited IDS 3/21/2024) (“Klunker”).
The instant claims are drawn to a method for the treatment of an immune complex-mediated disease in a subject comprising administering to the subject an anti-CD38 antibody or antibody fragment, wherein the antibody comprises an HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NOs: 1-3, respectively; an LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 4-6, respectively; and VH and VL amino acid sequences of SEQ ID NOs: 7-8, respectively, wherein the antibody is administered intravenously.
The teachings of Campbell are set forth above.
Campbell does not teach the anti-CD38 antibody amino acid sequence recited in instant claims 5-6, or intravenous administration.
Klunker teaches the anti-CD38 antibody known as MOR202 for the treatment of autoantibody-mediated membranous nephropathy, comprising the heavy and light chain CDR amino acid sequences of SEQ ID NOs: 1-6 and VH/VL amino acid sequences of SEQ ID NOs: 7-8, respectively [pg. 24; instant claims 5-6]. In addition, Klunker teaches the antibody can be administered intravenously [pg. 27, lines 5-8; instant claim 16]. The administered anti-CD38 antibody binds to and depletes CD38 expressing antibody-secreting cells [pg. 34], including those deposited in the kidneys [pg. 39, lines 16-20].
The MOR202 antibody taught by Klunker has the identical amino acid sequence of the antibody recited in instant claims 5-6 with the identical CDR amino acid sequences of SEQ ID NOs 1-6.
It would have been obvious to one of ordinary skill in the art to select the amino acid sequence of an anti-CD38 antibody that has previously been shown to be effective in treatment of nephropathy from those taught in the prior art, such as MOR202. A skilled artisan would have a reasonable expectation of success in selecting the dosing protocol for MOR202 taught by Klunker as a starting for treating immune complex-mediated diseases, as it has already been shown to be effective in the treatment of other autoimmune diseases, including those that affect the kidneys as evidenced by Klunker. Accordingly, the combination of prior art references provided a prima facie case of obviousness.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642