tNotice 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
Claims 1-25, 28-38 are currently pending. Claims 1-25, 28 have been amended. Claims 26-27 are canceled. Claims 29-38 are new. Claims 1-25, 28-38 will be examined on the merits herein.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Japan on February 18, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement (IDS)
The IDS submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 5, 11, 13 are objected to because of the following informalities:
Claims 1, 5, 11, 13 are reciting “an amino acid sequence of”, however it appears to mean “the amino acid sequence of”. “The” is interpreted to mean “this one, and no others” but “An” can mean “a sequence within”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 28-30, 35-38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating rheumatoid arthritis or arthritis, systemic lupus erythematosus, lupus nephritis, or graft-versus-host disease by administering an effective amount of the anti-PAD4 antibody or the antibody fragment thereof, does not reasonably provide enablement for preventing the diseases recited in these claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The instant claims encompass a method of preventing rheumatoid arthritis or arthritis, systemic lupus erythematosus, lupus nephritis, or graft-versus-host disease, however the specification does not teach the prevention of these diseases said to be preventable by the applicant’s method as in claims 28-30, 35-38. The applicability of the method for preventing all the diseases asserted in the claims mentioned above is unknown and/or not readably reproducible by the artesian. In the specification, the applicant disclaims that the term “prevention” includes “preventing development of the above diseases in mammals, especially humans” (page 12, [0112]) and that “preventing recurrence” includes “preventing recurrence of those diseases that repeat remission and recurrence in mammals, especially humans” (see page 12; [0113]). However, there are no teachings in the specification regarding the claimed method for preventing the diseases recited in the claims by administering the anti-PAD4 antibody or its fragment thereof in health patients with predisposition to develop the diseases as in claims 28-30, 35-38.
Although, the use of anti-PAD4 antibody is recited in the specification for preventing the recurrence of disease, the term “prevent” is interchangeable with “treat”, because the patient had already developed the disease, and ultimately the continuous use of medication is intended to avoid recurrence of disease, which is well-known in the art. Also, it is well-known in the art that the diseases recited in the claims are autoimmune diseases, and have a genetic component that makes impossible to completely prevent the disease before onset symptoms in health patients. There are no teachings regarding any interventions in the subject matter’s genetic components in order to prevent the development of onset symptoms. The enablement of scope requirement is not fulfilled by the applicant, since a person of ordinary skill in the art cannot make or use the full scope of the claimed invention without undue experimentation.
In order to comply with the enablement of scope requirement, the applicant must fully disclosure the method of preventing rheumatoid arthritis or arthritis, systemic lupus erythematosus, lupus nephritis, or graft-versus-host disease prior its development in the subject matter in the specifications.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
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.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
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.
Thus, the method of preventing in claims 28-30, 35-38 must be able to completely eliminate the development of diseases recited in 28-30, 35-38. It is apparent that there is no full scope of requirement, because two methods are claimed, however the specification only enables a fraction of them, which is the method of treating.
Rose et al. (Noel R. Rose, Prediction and Prevention of Autoimmune Disease in the 21st Century: A Review and Preview, American Journal of Epidemiology, Volume 183, Issue 5, 1 March 2016, Pages 403–406, https://doi.org/10.1093/aje/kwv292) teaches that “autoinflammatory responses,” the disorders usually have a clear genetic component and evidence of activation of the innate immune system. Noel et al. also teaches that immunoregulatory genes, often expressed through particular cytokines and other inflammatory mediators, can enhance or limit disease in genetically susceptible animals selected on the basis of their MHC haplotype. Rose et al. teaches that beyond these genetic risk factors, many internal variables can shift an autoimmune response to greater or lesser probability of clinical disease. These variables include such factors as sex, age, pregnancy, and even neurologic and emotional signals. Noel et al. also teaches that after an amalgamation with genetic factors, characteristic autoantibodies are the best predictors of impending autoimmune disease at this time.
Yet, Dedmon et al. (Dedmon LE. The genetics of rheumatoid arthritis. Rheumatology (Oxford). 2020 Oct 1;59(10):2661-2670. doi: 10.1093/rheumatology/keaa232) teaches significant genetic variants associated with Rheumatoid arthrosis (RA) susceptibility, with particular focus on the contribution of the HLA class II genes across different ethnic groups. Dedmon et al. also teaches the potential applications of pharmacogenomics to RA management by identifying polymorphisms associated with variation in treatment response or toxicity. The response to treatment of autoimmune diseases varies widely between patients and has a genetic component. Dedmon et al. also teaches that early management with Disease-modifying antirheumatic drugs (DMARDs) and biologics can slow disease progression and improve outcomes. DMARDs are the first line of treatment for RA, and include MTX, sulfasalazine and azathioprine. They are frequently used in combination, and can take 6–12months to produce symptomatic improvement [5]. NICE guidelines mandate that patients may be prescribed biologics only if they continue to present with active RA despite having tried at least two different DMARDs [9]. Biologics include TNF-a inhibitors (infliximab, etanercept, adalimumab), B-cell depletors (rituximab), IL-1/IL-6 inhibitors (tocilizumab), and inhibitors of T-cell co-stimulation (abatacept). They are often used in combination with MTX [5]. Response to DMARDs and biologics is highly variable between patients, and biologics are still prescribed on a largely trial-and-error basis [10].
Partanen et al. (Partanen J, Hyvärinen K, Bickeböller H, Bogunia-Kubik K, Crossland RE, Ivanova M, Perutelli F, Dressel R. Review of Genetic Variation as a Predictive Biomarker for Chronic Graft-Versus-Host-Disease After Allogeneic Stem Cell Transplantation. Front Immunol. 2020 Oct 19;11:575492. doi: 10.3389/fimmu.2020.575492) teaches some of the candidate genes, in particular, CTLA4, HSPE, IL1R1, CCR6, FGFR1OP, and IL10, and some non-HLA variants in the HLA gene region have been replicated to be associated with Chronic Graft-Versus-Host-Disease (cGvHD) risk in independent studies. These associations should now be confirmed in large well-characterized cohorts with fine mapping. Some patients develop cGvHD despite very extensive immunosuppression and other treatments, indicating that the current therapeutic regimens may not always be effective enough. Partanen also teaches the need to focus on modern genome-level tools, such as machine learning, polygenic risk scores and genome-wide association study-transcription meta-analyses, instead of focusing on just single variants. The risk of cGvHD may be related to the summary level of immunogenetic differences, or whole genome histocompatibility between each donor-recipient pair. As the number of genome-wide analyses in HSCT is increasing, we are approaching an era where there will be sufficient data to incorporate these approaches in the near future.
Therefore, neither the art nor the specification teaches how to prevent the diseases in claims 28-30, 35-38. Thus, one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claims 28-30, 35-38 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 28-30, 35-38 contain 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 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 8, 11 and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 8 and 11 are reciting “the 84th amino acid of the heavy chain”, which is a serine. However, no reference sequence was provided in order to clarify where the residue 84th is located in the amino acid sequence. Therefore, the 84th amino acid residue is indefinite.
Claim 16 refers to a product, antibody. However, the claim recites “cleavage occurring during generation is less than 3%” means”, which implies a method of making an antibody. Therefore, this recitation in the claim is unclear in reference to a product.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 23-25 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 23-25 fail to further limit the subject matter of the claims from which they depend. The limitations in the claims recite the intended use of “a pharmaceutical composition” of claim 22 and do not provide a further limit on claim 22.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
Claims 1-7, 9-10, 12-15, 17-22 are allowable.
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
Harris teaches association of autoimmunity to peptidyl arginine deiminase type 4 (PAD4) with genotype and disease severity in rheumatoid arthritis.
Burska teaches autoantibodies to posttranslational modifications in rheumatoid arthritis.
Bradbury teaches the in vitro display technologies, and that many of the antibodies derived using in vitro display methods. Bradbury also teaches the scope of in vitro display technologies and what they have enabled, in particular in the context of distinguishing subtle differences in protein sequences and conformations or even minor changes in the chemical structural of small molecules.
Fujino teaches a robust in vitro affinity maturation strategy based on interface-focused high-throughput mutational scanning. Fujino also teaches the strategy of two steps beginning with identification of beneficial single amino acid substitutions then combination.
Saito teaches the six anti-PAD4 antibody clones, A11, E9, G6, G8, G9 and H7 isolated separately from a scFv phage library and that the six antibodies have sequence similarity in their CDRs. Saito also teaches that clone G8 exerted an increased therapeutic effect on RA and the humanized anti-PAD4 antibodies derived from G8.
Lippow teaches computational design of antibody-affinity improvement beyond in vivo maturation.
Warszawski teaches optimizing antibody affinity and stability by the automated design of the variable light-heavy chain interfaces.
The prior arts teach that autoimmunity in rheumatoid arthritis (RA) is directed against a polymorphic molecule genetically associated with the disease, the PADI4 gene (PAD4 protein). Also, the prior arts teach that the epitopes targeted include the polymorphic region itself, and autoantibodies to this molecule are associated with susceptibility polymorphisms. In addition, post-translational modifications such as citrullination, carbamylation, and oxidation introduce neoepitopes in proteins that can generate novel autoantibody specificities and are associated with RA. Also, the prior arts teach the use of protein engineering as a powerful tool to create new antibodies by using DNA recombinant technologies such as site-directed and directed random mutagenesis. The application of these technologies via the phage-display method which is extensively used to create libraries of antibodies such as anti-PAD4 antibodies, resulting in the evolved antibody, the clone G8.
However, the novel PAD4 antibody, which are mutated sequence versions of G8 clone of Saito disclaimed in the present invention is an innovative step because there is no indication that the alterations made in the CDR sequences of G8 clone would result in the new features to the G8 antibody in any of the prior arts searched for the purpose of this examination.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PRICILA HAUK TEODORO whose telephone number is (571) 272-2784. The examiner can normally be reached M-F 6:15AM-3:15PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel Kolker can be reached at (571) 272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PRICILA NMN HAUK TEODORO/ Examiner, Art Unit 1645
/DANIEL E KOLKER/ Supervisory Patent Examiner, Art Unit 1645