DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims 1, 11, 19-21, 23, 25, 27, 29, 43, 51, 59, 68, 74-75, 82, 84, 98, 107-108 and 111 are pending.
Election/Restrictions
Applicants' election without traverse of Group II, claims 19-21, 23, 25, 27, 29, 43, 51, 59, 68, 74-75, 82, 84, 98 and 111, in the reply filed on 1/26/26 is acknowledged. Claims 1, 11 and 107-108 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
The elections without traverse of (1) light chain amyloidosis as the species of amyloidosis, and (2) daratumumab as the species of additional therapy, in the reply are also acknowledged. Claims 59, 82, 84, 98 and 111 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 19-21, 23, 25, 27, 29, 43, 51, 68 and 74-75 are under consideration, as they read upon the elected species.
Specification
The disclosure is objected to because of the following informalities:
The title of the invention, “Method of Treating Amyloidosis” is not descriptive because it is directed generally to any means for treating amyloidosis, but the claims are limited to treatment with an antibody that binds to light chains. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “Method of Treating Amyloidosis with an Antibody that Binds to Light Chains”.
Appropriate correction is required.
Claim Objections
Claims 19-21, 24, 25, 27, 29, 43, 51 and 74-75 are objected to for the following informalities:
In claim 19, line 2, “500 to 1,000 mg/m2” should be “500 mg/m2 to 1,000 mg/m2”, as in claims 29, 51, 68 and 74.
In claim 21, line 1, “antibody” should be “the antibody”; compare with claim 20.
Claims 29, 43, 51 and 74-75 are objected to for depending from non-elected inventions. Each of these method claims requires administration of the composition of claim 1, which is part of a non-elected group, Invention I. The elected group, Invention II, is directed to process claims, and therefore the product claims of Invention I are not eligible for rejoinder. The process claims should be amended to stand alone by incorporating the limitations of the products to be used.
Appropriate correction is required.
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.
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 19-21, 23, 25, 27, 29, 43, 51, 68 and 74-75 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 19, 29, 51, 68 and 74 are indefinite with regard to the recitation of “about 500 mg/m2 to 1,000 mg/m2" due to the use of the term "about". Per MPEP 2173.05(b)(III)(A), “In determining the range encompassed by the term “about”, one must consider the context of the term as it is used in the specification and claims of the application”. In the instant case, the specification does not define the term, either with respect to dosages or generally, and instead merely uses the term in the same manner as the claim, e.g., at ¶ 16 (published application). The specification does not provide any guidance such that the skilled artisan would know which doses are encompassed by the claim. Thus, due to the use of the term "about", the claim is indefinite as to what degree of variation is encompassed; for example, "about 500 to 1000" could encompass a range of integers 499 to 1001, 450 to 1050, or 250 to 1,500, to list several of the many alternate possibilities. For purposes of advancing prosecution, the term is interpreted as encompassing each of the alternate possibilities that the indefinite term reads upon.
Claim 23 is indefinite with regard to the recitations of “about 1,000 mg/m2”, “about 20-25 mg/kg” and “about 2,750 mg” for each use of the term “about” for the same reason as for the use of the term in parent claim 19.
Claim 23 is also indefinite because it further limits “administering a weekly dose of about 1,000 mg/m2 of antibody”, but parent claim dose not refer to a weekly dose. It is further unclear how a dosage that is given in “mg/m2”, which is mass per body surface area of the subject can be limited to a dose of 20-25 mg/kg, which is mass per weight of weight of the subject.
The remaining claim(s) included in the rejection are dependent claims that depend from one of the claims rejected above, and encompass the same indefinite subject matter.
Claim Rejections - 35 USC § 112(a), written description
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 19-21, 23, 25, 27, 29, 43, 51, 68 and 74-75 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.
The claims are directed to antibodies that are claimed as “an antibody having a heavy chain variable domain (VH) having an amino acid sequence of SEQ ID NO:1 and a light chain variable domain (VL) having an amino acid sequence of SEQ ID NO:2”. The language used with regard to these reference sequences results in the claimed antibodies failing to meet the written description requirement.
The phrases "having the amino acid sequence of SEQ ID NO: X" and "having an amino acid sequence of SEQ ID NO: X" result in claims of very different scope, because while the former encompasses only sequences that comprise the full length of SEQ ID NO: X, with or without additional amino acids at either or both ends, the latter encompasses sequences that comprise the full-length sequence of SEQ ID NO: X or any portion of SEQ ID NO: X; i.e., fragments of SEQ ID NO: X. The language in the instant claims follows that of the latter example, and as such the claim encompass antibodies that are defined by only portions of SEQ ID NO: 1 and/or 2. However, the specification does not describe which of these variants will retain the functionality of the antibody in binding to the light chains of antibodies, which is required for the antibody to be active in the claimed method of treatment.
The prior art recognizes that antibodies bind to epitopes of 5-7 amino acids (Benjamini et al, 1991. Immunology: A Short Course, 2nd edition, page 40 only). While the general structure of an antibody was well-known in the prior art, it is the structure of the complementarity-determining regions (CDRs) that determines the specificity of a particular antibody, and said CDR structure is not predictable based on the epitope to which it binds. Thus, even knowing the structure (CDRs) of one antibody does not allow the skilled artisan to predict the structure of other antibodies that bind to the same epitope or to the other epitopes in the same protein. The relevant art, Ferrara et al (2015. mAbs. 7(1): 32-41) teaches that there is substantial variation in the structure of antibodies that bind to a single protein, on the order of hundreds of different sequences; specifically, see page 36: "The number of different HCDR3s selected against the test antigens ranges from 74 to 460 (Table 3), with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (pg 36). Furthermore, the decision of the Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target molecule (e.g. the light chain of an antibody) is not in and of itself sufficient to provide a written description of the genus of antibodies binding to said target protein.
MPEP 2163 provides guidance for complying with the written description requirement of 35 U.S.C. 112(a) that the “specification shall contain a written description of the invention…”; this requirement is separate and distinct from the enablement requirement (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). Written description for a claimed genus may be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Written description for a claimed genus can also be satisfied when relevant identifying characteristics are disclosed. Per MPEP 2163, “[d]etermine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.” However, claiming by function does not necessarily satisfy the written description requirement. “[A] generic statement such as "vertebrate insulin cDNA" or "mammalian insulin cDNA," without more, is not an adequate written description of the genus because it does not distinguish the claimed genus from others, except by function. It does not specifically define any of the genes that fall within its definition. It does not define any structural features commonly possessed by members of the genus that distinguish them from others … A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. It is only a definition of a useful result rather than a definition of what achieves that result” (Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “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” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of anti-light chain antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only:
A method of claim 19-21, 23, 25, 27, 29, 43, 51, 68 or 74-75, wherein the administered antibody is antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 1 and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 2, but not the full breadth of the claims meet the written description provision of 35 U.S.C. §112(a).
Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
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 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.
Claim Rejections - 35 USC § 102
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.
Claims 19-21, 23, 25, 27 and 68 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lentzsch et al, U.S. Patent Application Publication 20190038745, published 2/7/19 (cited on the 1/22/24 IDS). The earliest date to which the instant application claims priority is 9/14/20.
Claim 19 encompasses a method of decreasing an amount of amyloid deposits in a subject comprising administering to the subject about 500 to 1,000 mg/m2 of an antibody having heavy chain and light chain variable domains having the amino acid sequences of SEQ ID NO: 1 and 2, thereby decreasing the amount of amyloid deposits in the subject.
Lentzsch teaches “[a] method of treating an amyloid deposit in a human patient in need of such treatment which comprises administering to the patient a pharmaceutical composition comprising a chimeric mouse-human antibody which comprises a VK region comprising SEQ ID NO: 47 and a VH region comprising SEQ ID NO: 48 in a dose effective to treat said amyloid deposition disease, together with a pharmaceutically acceptable carrier” (see claim 1). The sequences of SEQ ID NO: 47 and 48 are identical to instant SEQ ID NO: 1 and 2. Lentzsch further teaches that the dose can be about 500 mg/m2 (see claim 3, depending from claim 1; also ¶ 153). As such, the teachings of Lentzsch anticipate claim 19.
Claim 20 encompasses a method of claim 19 wherein the antibody is administered weekly for at least 2 weeks. Lentzsch further teaches that the antibody can be administered “twice weekly”, which is equivalent to once a week for two weeks (¶ 150). As such, the teachings of Lentzsch also anticipate claim 20.
Claim 21 encompasses a method of claim 19 further comprising administering a maintenance dose of antibody to the subject thereafter. The term “maintenance dose” is not further defined by the instant specification. Lentzsch teaches that the antibodies of the invention may be administered “once every week” for as long “as the situation or condition of the patient may indicate” (¶ 166), which is encompassed by the term “maintenance dose” as used in claim 21. As such, the teachings of Lentzsch also anticipate claim 21.
Claim 23 encompasses a method of claim 19 wherein administering a weekly dose of about 1,000 mg/m2 comprises administering about 20-25 mg/kg of antibody. Lentzsch further teaches that 20, 21, 22, 23, 24 or 25 mg/kg of antibody can be administered (¶ 155). As such, the teachings of Lentzsch also anticipate claim 23.
Claim 25 encompasses the method of claim 19 wherein the subject has been previously treated for an amyloidosis disease prior to administration of the antibody. Lentzsch further teaches that the compositions of the invention “may be administered to a patient that has previously received conventional treatment for amyloidosis and amyloid diseases, but who has not responded to conventional treatment” (¶ 120). As such, the teachings of Lentzsch also anticipate claim 25.
Claim 27 encompasses a method of claim 19 wherein the amyloidosis is light chain (AL) amyloidosis. Lentzsch further teaches treatment of a patient with AL amyloidosis (¶ 136). As such, the teachings of Lentzsch also anticipate claim 27.
Claim 68 encompasses a method of inhibiting aggregation of light chains and amyloid fibrils in a subject comprising administering to the subject about 500 to 1,000 mg/m2 of an antibody having heavy chain and light chain variable domains having the amino acid sequences of SEQ ID NO: 1 and 2, thereby inhibiting aggregation of light chains and amyloid fibrils in the subject. Lentzsch further teaches that the antibody functions by decreasing light chain fibril deposits (¶ 54). As such, claim 68 is met by the same teachings of Lentzsch that meet the limitations of claim 19. As such, the teachings of Lentzsch also anticipate claim 68.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
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 at the time any inventions covered therein were effectively filed 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 at the time a later invention was effectively filed 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 29, 43, 51 and 74-75 are rejected under 35 U.S.C. 103(a) as being unpatentable over Lentzsch et al, U.S. Patent Application Publication 20190038745, published 2/7/19 (cited on the 1/22/24 IDS), as applied to claim 19 above, and further in view of Li et al, 2014. Anal Chem. 86: 5150-5157.
Claim 29 encompasses a method of treating an amyloidosis disease in a subject comprising administering to the subject (a) the pharmaceutical composition of claim 1; and an additional therapy, thereby treating the disease, and wherein the antibody administration dose is from about 500 to 1,000 mg/m2. The composition of claim 1 comprises 4 components: (a) the antibody comprising SEQ ID NO: 1 and 2; (b) one or more isotonic agents; (c) a buffer; and (3) a non-ionic surfactant.
As set forth above for claim 19, Lentzsch teaches a method of treating an amyloidosis disease in a subject comprising a pharmaceutical composition comprising an antibody having the amino acid sequence of SEQ ID NO: 1 and 2, and a pharmaceutically acceptable carrier, and wherein the antibody administration dose is 500 mg/m2. Lentzsch further teaches that the pharmaceutical carriers of the invention may include isotonic agents, buffers and surfactant (¶ 117). Lentzsch further teaches that the “[t]he disclosed methods of treatment may also be combined with other known methods of treatment as the situation may require” (¶ 156). Lentzsch further teaches that carriers may include surfactants (¶ 118). Thus, Lentzsch teaches all of the limitations of claim 29, except that the surfactant is a non-ionic surfactant.
Li teaches “Polysorbate 20 (often referred by its trade name Tween 20) is a nonionic surfactant commonly used in the formulation of therapeutic monoclonal antibodies (mAb) due to its biocompatibility, low toxicity, and good stabilizing properties for proteins … The role of polysorbate 20 in protein formulations is to prevent the formation of aggregates and protect proteins from denaturation” (page 5150).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to take the method treating amyloidosis by administering (1) a pharmaceutical composition comprising an antibody comprising SEQ ID NO: 1 and 2, an isotonic agent, a buffer and a surfactant, wherein the antibody dose is 500 mg/m2, and (2) an additional therapy, that is taught by Lentzsch, and modify it to use Polysorbate 20 as the surfactant. The person of ordinary skill in the art would have been motivated to make such a change because Lentzsch suggests use of a surfactant, but does not specify a specific types, and Li teaches a specific type of surfactant that is commonly used in preparations of antibodies for administration. The person of ordinary skill in the art would have had a reasonable expectation of success because Li teaches use of polysorbate 20 for any antibody in general, and thus the person of ordinary skill in the art would reasonably expect to work in a formulation of the antibody taught by Lentzsch. This rationale supports a prima facie conclusion of obviousness in accord with KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (2007).
Claim 43 encompasses a method of claim 29 wherein the additional therapy is a stem cell transplant. Lentzsch further teaches that “[t]he current standard of care for AL amyloidosis, for example, generally involves autologous blood stem cell transplantation (ASCT) or an autologous bone marrow transplant” (¶ 156). As such, it would have further been obvious to employ a stem cell transplantation as the additional therapy taught by Lentzsch when practicing the modified method obvious over the teachings of Lentzsch in view of Li that meets the limitations of parent claim 29.
Claim 51 encompasses a method of treating an amyloidosis disease involving a heart in a subject comprising administering to the subject the composition of claim 1, thereby treating the disease, wherein the dose is from about 500 to 1,000 mg/m2. Lentzsch further teaches that the method encompassed by claim 1 also includes a primary amyloidosis involving the heart; see dependent claims 2 and 6. Lentzsch further teaches that the methods of the invention include “methods of improving myocardial function in patients diagnosed with amyloid light chain amyloidosis (ALA) that includes cardiac involvement (i.e., amyloid deposition in or around the heart)” (¶ 4). As such, it would have further been obvious to treat a subject having light chain amyloidosis with cardiac involvement when practicing the modified method obvious over the teachings of Lentzsch in view of Li that meets the limitations of parent claim 29.
Claim 74 encompasses a method of treating an amyloidosis disease in a subject comprising administering the pharmaceutical compositions of claim 1, thereby treating the disease, wherein the dose of antibody is from about 500 to 1,000 mg/m2. This method fully encompasses that of instant claim 29, and therefore the limitations of claim 74 are also met by the method obvious over the teachings of Lentzsch in view of Li that meets the limitations of claim 29.
Claim 75 depends from claim 74 and limits the parent claim by means of a wherein clause. This wherein clause has been fully considered in context of the entire claim, but does not render the claimed method patentably distinct from a method obvious over the prior art because it simply expresses the intended result of a process step positively recited. See MPEP 2111.04, which states that a "whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited" (Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), quoting Minton v. Nat ’l Ass ’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). Specifically, in claim 75, the claim simply expresses the intended result (rendering the subject eligible for a stem cell transplant) of a process step positively recited (administering the pharmaceutical composition). As such, the method obvious over the teachings of Lentzsch in view of Li that meets the limitations of parent claim 74 also meets the limitations of claim 75.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674