DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is a 35 U.S.C. 371 national phase application and claims priority to International Application No. PCT/EP2021/087779 (filing date 12/29/2021), which claims the benefit of the prior-filed European Provisional Patent Application No. EP20217536.0, filing date 12/29/2020.
Status of Application/Claims
The preliminary amendment, filed 03/15/2024, is acknowledged. Claims 1-10, 14-15, 17, 23-29, 31-32, 34, 36-45, and 47-48 are canceled. Claims 11-13, 16, 18, 20, 30, 33, and 35 are currently amended. Claims 49-55 are new. Claims 11-13, 16, 18-22, 30, 33, 35, 46, and 49-55 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/03/2024 has been fully considered by the examiner.
Drawings
The drawings are objected to because Figures 15A, 15C and 15D are missing images associated with the labels shown and/or disclosure figure descriptions. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Figures 15A, 15B, 23A, 23B, and 23C contain amino acid sequences with no associated SEQ ID NOs.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The use of the terms Megalign, Biacore, Invitrogen, GeneBio, Phenyx, Matrix Sciences, Mascot, Skyline, Percolator, Sequest, Adipogen, and Merck, which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Hyperlink is found on p.87, line 7:
“https://www.uniprot.org/” contains a prefix (underlined)
Claim Objections
Claim 12 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 30 is objected to because of the following informalities: Claim 30 recites, “…is quantified us a nephelometric assay…” which should be corrected to “…is quantified using a nephelometric assay…”. 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 21-22, 30, 35, and 53-55 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 recites the limitation "the mixture" in line 6. There is insufficient antecedent basis for this limitation in the claim.
Claim 22 recites the limitation "the mixture" in line 6. There is insufficient antecedent basis for this limitation in the claim.
Claim 30 recites the limitations "the mixture" in lines 6 and 7 (two instances) and “the irradiation step” in lines 7-8 (one instance). There is insufficient antecedent basis for these limitations in the claim.
Claim 35 is dependent on claim 33. Claim 33 recites “method for predicting and/or diagnosing.” However, claim 35 recites the limitation "the method for determining whether a subject is susceptible to the treatment” in lines 1-2 and “the treatment” in line 7. Thus, there is insufficient antecedent basis for the above limitations in claim 35. For further examination, claim 35 is interpreted to further limit the “method for predicting and/or diagnosing” of claim 33.
Claim 53 recites the limitation "the proteoglycans" in lines 1 and 2 (two instances). There is insufficient antecedent basis for this limitation in the claim.
Claim 54 recites the limitation "the interaction" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 55 recites the limitation "the interaction" in line 2. There is insufficient antecedent basis for this limitation in the claim.
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 33 and 35 are rejected under 35 U.S.C. 101 because the claimed
invention is directed to abstract ideas with judicial exceptions without significantly
more. The claims are drawn to methods comprising abstract ideas. The judicial exception is not integrated into practical application because the claims read on abstract ideas. The claims do not include additional elements that are sufficient to amount to
significantly more than the judicial exceptions.
The claims are evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106.III.
Step 1: Is the claim drawn to a process, machine, manufacture or composition of matter?
Yes. Claim 35 is dependent on claim 33, and the claims are drawn to a method/process (i.e., for predicting and/or diagnosing diseases or conditions) which is one of the four statutory categories.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. With respect to claim 33, the method for predicting and/or diagnosing comprises the following steps:
(a)…determining the concentration…
(b)…comparing the concentration to a reference value…
(c)…predicting and/or diagnosing a disease or condition based on the comparison…
With respect to claim 35, which is intended to further limit the method of claim 33, the recited “method” of claim 35 comprises the following steps: (a)…determining the concentration… (b)…determining that said subject is susceptible to the treatment…
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into an application?
No. The claims 33 and 35 do not recite additional elemental steps that would integrate the judicial exception into an application.
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. There are no additional recited elements that amount to significantly more than the human mental processes of “determining,” “comparing,” and “predicting and/or diagnosing” recited in the claims. While claim 35 recites “the treatment,” this term lacks proper antecedent basis and is not described by any step that amounts to significantly more than the judicial exceptions. Therefore, the claims encompass abstract ideas related to mental processes.
Without any evidence to the contrary, the method does not include any steps other than those listed above, which are mental processes. Because there are no additional steps that integrate the judicial exceptions of abstract ideas into an application that amounts to significantly more than the judicial exceptions, the claimed invention does not pass the “Subject Matter Eligibility Test for Products and Processes” (See, e.g., MPEP 2106).
Accordingly, the claims are directed to judicial exceptions. Because the claim
does not include any additional features that could add significantly more to the
exception, the claim does not qualify as eligible subject matter under 35 U.S.C §101.
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.
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 11, 13, 16, 18-20, 33, 35, and 49-55 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 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. THIS IS AN ENABLEMENT REJECTION.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not ‘experimentation.’” (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: The nature of the invention; the breadth of the claims; the amount of direction provided by the inventor; the existence of working examples; the state of the prior art; the level of predictability in the art; the quantity of experimentation needed to make or use the invention based on the content of the disclosure; and, the level of one of ordinary skill. While all of these factors are considered, a sufficient amount for amount for a prima facie case are discussed below.
The nature of the invention
Claim 11 is drawn to an antibody, or antigen binding fragment thereof, wherein only VH CDR3 and VL CDR3 regions are defined.
Claim 13 is drawn to the antibody, or antigen binding fragment thereof, wherein the VH and VL chains are defined only by 90% identity.
Claim 16 is drawn to a polynucleotide that encodes the antibody or antigen binding fragment of claim 11.
Claim 18 is drawn to a pharmaceutical composition of the antibody or antigen binding fragment thereof of claim 11.
Claims 19-20 recite additional therapeutic agents in the composition comprising the antibody or antigen binding fragment of claim 11.
Claim 33 recites a method for predicting disease. Claim 35 is dependent on claim 33 and does not overcome the issue.
Claims 49-51 are drawn to methods of preventing disease.
Claims 52-53 are drawn to additional limitations for the method of preventing disease, wherein the antibody or antigen binding fragment’s ability to increase interaction of APRIL with proteoglycans.
Claims 54-55 are drawn to additional limitations for the method of preventing disease, wherein the antibody or antigen binding fragment modulates APRIL binding to receptors.
The breadth of the claims
Claim 11 is broad in that the antibody or antigen binding fragment only requires that the VH CDR3 and VL CDR3 regions are defined by the SEQ ID NOs recited in claim 11. Claims 13, 16, and 18-20 are dependent on claim 11 and do not overcome the issue.
Claim 33 is broad in that it encompasses prediction of hypertriglyceridemia, metabolic syndrome, non-alcoholic steatohepatitis, diabetes mellitus type 2, atherogenic dyslipidemia, cardiovascular events and/or atherosclerosis. Claim 35 is dependent on claim 33 and does not overcome the issue.
Claim 49 recites a method of preventing disease comprising administering to a subject an effective amount of an APRIL antibody. The claim is broad in that it encompasses prevention of multiple diseases and/or conditions: hypertriglyceridemia, metabolic syndrome, non-alcoholic steatohepatitis, diabetes mellitus type 2, atherogenic dyslipidemia, abdominal aortic aneurysm, cardiovascular events and/or atherosclerosis. Claims 50-55 are dependent on claim 49 and do not overcome the issue.
The amount or direction provided by the inventor/ the existence of working examples
Regarding claim 11 (and, thus, also claims 13, 16, and 18-20), the specification teaches the VH and VL amino acid sequences for 8 antibodies: Aprily 1 (instant VH SEQ ID NO: 42 and instant VL SEQ ID NO: 46), Aprily 2 (instant VH SEQ ID NO: 49 and instant VL SEQ ID NO: 53), Aprily 5 (instant VH SEQ ID NO: 56 and instant VL SEQ ID NO: 60), “104” (instant VH SEQ ID NO: 7 and instant VL SEQ ID NO: 11), “108” (instant VH SEQ ID NO: 14 and instant VL SEQ ID NO: 18), “110” (instant VH SEQ ID NO: 21 and instant VL SEQ ID NO: 25), “115” (instant VH SEQ ID NO: 28 and instant VL SEQ ID NO: 32), and “2C8” (instant VH SEQ ID NO:35 and instant VL SEQ ID NO: 39). The VH CDR3 and VL CDR3 regions recited in claim 11 a) through e) correspond to instant antibodies 104, 108, 110, 115, and 2C8, respectively and specifically.
Regarding claims 33 (and, thus, also claim 35) and claim 49 (and, thus, also claims 50-55), the specification teaches APRIL antibody staining of atherosclerotic arteries (Fig.1); APRIL antibody treatment in animals having hypertriglyceridemia (Fig.4) and high liver triglycerides (Fig.6); macrophage content in atherosclerotic plaques of animals having hypertriglyceridemia (Fig.5); and, aortic diameters in WT versus Tnfsf13 KO animals following abdominal aortic aneurysm (AAA) induction (Fig.19). The specification does not teach that administration of any APRIL antibody is able to predict and/or prevent any of the recited diseases or conditions. There is no support in the disclosure providing evidence that disease is predicted/prevented.
Regarding claim 49 (and, thus, also claims 50-55), the disclosure does not provide any evidence for prevention of disease.
The state of the prior art/ the level of predictability in the art
Regarding claim 11 (and, thus, claims 13, 16, and 18-20), the instant specification teachings do not enable the full breadth of the claims because the art doesn’t teach any antibodies that minimally have CDR3s of the VH and VH chain; thus, the art doesn’t teach what antigen the recited antibody can bind to and the antibody would not predictably bind an antigen. Therefore, claims 11, 13, 16, and 21-20 are rejected because the claims do not enable one skilled in the art to predictably use the antibody.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (see Paul, Fundamental Immunology, 3rd Edition: Fv Structure and Diversity in Three Dimensions, 1993, p. 292-295; herein referred to as Paul). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, p.293, col., lines 3-8 and line 31 – col.2, line 9 and lines 27-30).
Additionally, Bendig M. M. Methods: A Companion to Methods in Enzymology, 1995; 8, p.83-93 (herein referred to as Bendig) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (p. 86, col.2, para.2). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figs.1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six CDRs, or where the CDR regions are not defined, would produce an antibody/antigen binding fragment. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of an antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict how to make the claimed antibodies.
Regarding claim 33 (and, thus also claim 35) and claim 49 (and, thus also claims 50-55), the prior art teaches that there are no recognized methods that can be used to establish that the diseases and/or conditions recited by the claim could be predicted and/or prevented using the claimed therapeutic methods. Additionally, there are no art recognized methods that could be used to identify subjects who would have predictably developed the diseases and/or conditions in order to determine that the disease and/or condition was predicted and/or prevented using the claimed methods.
For example, Parhofer and Laufs. The diagnosis and treatment of hypertriglyceridemia. Dtsch Arztebl Int (2019), 116, p.825-832 (herein referred to as Parhofer) teaches the association of hypertriglyceridemia (HTG) with overweight, metabolic syndrome, diabetes mellitus, atherosclerosis, and cardiovascular risk (abstract; p.826, col.1, para.3). Parhofer teaches that HTG is often discovered incidentally, that the severity of HTG varies widely, and that there is no uniform classification of the condition (abstract; p.825, col.1, para.1). Parhofer further teaches that triglyceride (TG) levels can fluctuate widely within an individual which further complicates diagnosis and treatment. Additionally, Parhofer teaches that genetics and lifestyle factors play a role in HTG and that HTG can occur during childhood or adulthood (p.826, col.1, para.1). Parhofer teaches diagnosis, management, lifestyle modifications, and drugs associated with interventions to treat of HTG (see entire document).
Regarding claim 49 (and, thus also claims 50-55): the prior art further teaches that APRIL antibodies have been used for treatment of diseases including hypertriglyceridemia (see Parhofer above) and autoimmune disease (see, for example Nakayamada, et al. BAFF- and APRIL-targeted therapy in systemic autoimmune diseases. Inflammation and Regeneration (2016), 36:6, p.1-6; herein referred to as Nakayamada). However, the prior art does not teach prevention of disease using an APRIL antibody or antigen-binding fragment thereof.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Regarding claim 11 (and, thus, claims 13, 16, and 18-20): In order to make an antibody that could predictably be used to bind an antigen using only the VH CDR3 and VL CDR3 regions of the instant disclosure, one of ordinary skill would need to perform extensive undue experimentation.
Regarding claims 33 (and, thus, also claim 35) and claim 49 (and, thus, also claims 50-55): The examples of the instant disclosure studied treatment of hypertriglyceridemia and the effect of genetic APRIL depletion on AAA; and, the prior art teaches treatment of HTG. Based on the disclosure and the prior art, there is no known or disclosed method through which an ordinarily skilled artisan would have been able to predictably identify subjects who would have developed HTG or to predictably identify subjects who would have developed HTG in order to determine that HTG was prevented using the claimed methods. Therefore, in order to practice the invention as claimed, an ordinarily skilled artisan would have to participate in undue experimentation to determine a method that would allow for the prediction and/or prevention of HTG.
Regarding claim 49 (and, thus also claims 50-55): There are no art recognized methods that could be used to establish that the recited diseases were prevented using the claimed therapeutic method of administering an APRIL antibody or antigen-binding fragment thereof. Additionally, there are no art recognized methods that could be used to identify subjects who would have definitely and predictably developed disease in order to determine that the disease was prevented using the claimed method.
The level of one of ordinary skill
Regarding claims 11, 13, 16, 18-22, 33, 35, 46, and 49-55: The level of skill of one skilled in this art is high.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Paul, Bendig, LSBio, and Parhofer; and, the lack of guidance and direction provided by applicant, and the absence of working examples, undue experimentation would be required to practice making and/or using functional antibodies that selectively bind nc-APRIL versus nc-APRIL and c-APRIL, as well as antibodies that comprise fewer than all six CDRs with a reasonable expectation of success, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, and that the methods steps for using antibodies, are commensurate in scope with the claimed invention.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Claims 11, 13, 16, 18-22, and 46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. THIS IS A WRITTEN DESCRIPTION REJECTION.
Regarding claims 11, 13, 16, and 18-20: Claims 13, 16, and 18-20 are dependent on claim 11, and claim 11 is inclusive of a large genus of antibodies, or antigen binding fragments thereof that are recited to comprise VH and VL chains wherein only the CDR3 regions for each of the VH and VL chains is defined. Further, claim 13 further limits claim 11 by requiring only 90% identity to the recited VH and VL chains and allows for variability in the CDR regions.
Regarding claims 21 and 22: Claims 21 and 22 are inclusive of first and second antibodies that are defined only by functional descriptions of binding a first epitope and second epitope, respectively; and, of nc-APRIL or nc-APRIL and/or c-APRIL, respectively.
Regarding claims 46: The claim is inclusive of a large genus of antibodies, or antigen binding fragments thereof, that are defined only by the function description of specifically binding an epitope of APRIL of amino acid SEQ ID NO: 64 or SEQ ID NO: 96.
However, regarding claims 11, 13, 16, and 18-20, the written description in this case only sets forth only 8 structural examples for antibodies in the specification. The specification does not disclose, and the art does not teach, the genus of antibodies, or antigen binding fragments thereof, as is broadly encompassed in the claims.
Regarding claims 21-22 and 46, the specification teaches the 8 antibodies discussed above (i.e., Aprily 1, Aprily 2, Aprily 5, 104, 108, 110, 115, and 2C8) as well as the use of existing commercial antibody ELISAs (i.e., Adipogen® ELISA and Invitrogen® ELISA). The specification teaches that Aprily 1 and Aprily 2 bind the APRIL epitope defined by instant SEQ ID NO: 64 and that Aprily 5 binds a different epitope defined by instant SEQ ID NO: 96 (see Fig.15B). The disclosure further states that antibody “…108 targets the TACI-binding site of APRIL…” (p.82, Example 9). The disclosure does not otherwise provide for any antibody epitopes detected by the antibodies of the disclosure. The disclosure does state that “The inventors developed a home-made ELISA assay to be able to detect nc-APRIL (Fig.10) by using a combination of the anti-human APRIL Abs; Aprily 5, Aprily 2 and Aprily 1…” (see p.82, Example 10; Fig.10).
As described above, the prior art teaches that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (see Paul and Bendig above). Further, Hummer, A.M., et al. Advances in computational structure-based antibody design Current Opinion in Structural Biology (2022), 74:102379, p.1-7 (herein referred to as Hummer), demonstrates ongoing unpredictability between antibody binding and epitopes. Specifically, Hummer teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (p.1, col.2, para.2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (p.1, col.2, para.3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (p.4, . col.2, para.3). Thus, Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure and function. Thus, one of ordinary skill in the art could not produce an antibody structure that would predictably bind an antigen of SEQ ID NO: 64 or 96.
Claims 11, 13, 16, and 18-20 encompass a large genus of antibodies. However, the written description only reasonably conveys amino acid sequence structures for the 8 antibody VH and VL fragments as discussed in the 112(a)-enablement rejection above: Aprily 1, Aprily 2, Aprily 5, 104, 108, 110, 115, and 2C8.
Claims 21 and 22 recite methods that encompass a large genus of antibodies and epitopes that are not defined in order to support the claimed structure/function relationships recited.
Claim 46 encompasses an antibody or antigen binding fragment is stated to bind APRIL epitopes of SEQ ID NOs: 64 or 96, however the disclosure only provides support that SEQ ID NO: 64 is the minimal epitope for Aprily-1 and Aprily-2 and that SEQ ID NO: 96 is the minimal epitope for April-5. The minimal CDR1, 2, and 3 structures for the VH and VL for Aprily-1, Aprily-2, and Aprily-3 are defined and the structure/function relationship for these antibodies is supported by the disclosure. While the disclosure additionally provides the CDR structures for 5 additional antibodies, the structure/function relationship is not supported. The prior art teaches that commercial APRIL antibodies are available that do not correspond to either the epitope of instant SEQ ID NOs: 64 or instant SEQ ID NO: 96. For example, LSBio –LC-C382090 Human TNFSF13 Antibody, Nov. 2021. Internet – Wayback Machine. p.1-3 (herein referred to as LSBio) teaches an APRIL antibody generated against APRIL amino acid positions 120-200, which does not overlap completely with either the 102-108 epitope region for Aprily 5 or the 122-127 epitope region for Aprily 1/Aprily 2 (see LSBio p.2 versus instant Fig.15B). Thus, the disclosure does not provide sufficient written description for the full scope of antibody, or antigen-binding fragment thereof, as is broadly claimed.
Regarding written description for product claims 11, 13, 16, 18-20, and 46: A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.”
The inventions at issue in Lilly were DNA constructs per se, the holdings of that case are also applicable to claims such as those at issue here. Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of antibodies that encompass the genus of antibodies as recited in the claims nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.
Because the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus of antibodies, and because the genus is highly variant, the disclosure of the 8 antibodies discussed above is insufficient to describe the genus for the antibodies of claims 1 and 46. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.”Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Regarding written description for methods claims 21 and 22: The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). The issue is whether a person skilled in the art would understand the inventor to have invented, and been in possession of, the invention as broadly claimed. In LizardTech, claims to a generic method of making a seamless discrete wavelet transformation (DWT) were held invalid under 35 U.S.C. 112, first paragraph, because the specification taught only one particular method for making a seamless DWT and there was no evidence that the specification contemplated a more generic method. "[T]he description of one method for creating a seamless DWT does not entitle the inventor . . . to claim any and all means for achieving that objective." LizardTech, 424 F.3d at 1346, 76 USPQ2d at 1733. (see MPEP 2161).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
[AltContent: textbox (Instant SEQ ID NO: 28 species ‘115 VH’ vs. Da Silva SEQ ID NO: 4
[img-media_image1.png])]An antibody, or antigen binding fragment thereof, wherein the antibody comprises the CDR 1-3 regions for the VH and VL chains defined by the following SEQ ID NOs recited below are free of the prior art at 100% identity. The closest prior art to any of the VH or VL chains for antibodies with defined CDR regions outlined in the disclosure is provided by Da Silva, et al. – WO2015054600A2 (herein referred to as Da Silva) SEQ ID NO: 4 at 90.1% identity to instant VH chain of instant SEQ ID NO: 28 which comprises instant CDR1 SEQ ID NO: 29 (i.e., GFSLSTFGLG), instant CDR2 SEQ ID NO: 30 (i.e., IWWDDDN), and instant CDR3 SEQ ID NO: 31 (i.e., SRAHYYDGIHFDF) (see alignment below).
Conclusion
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647