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 .
Claims 1-19 and 21 are pending and under examination.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) filed on 4/20/2023 and 9/8/2023 have been considered.
It is noted to applicant that the specification at pg. 9 defines “active fragment” as any portion of flagellin as a fragment of 50, 75, 100 amino acids but the claims recite “a fragment” that can be 5,10, 20 or 30 amino acids in length of flagellin. Additionally, the term “any variant of flagellin” is interpreted by the examiner as any variant having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or higher variation in a flagellin protein.
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 1-15, 17-19 and 21 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.
The written description in this case only sets forth a composition comprising a fusion protein comprising flagellin and an immunoglobulin Fc region for treatment of non-alcoholic fatty liver disease, and therefore the written description is not commensurate in scope with “a fusion protein comprising any fragment or any variant of flagellin and an Fc region for prevention or treatment of non-alcoholic fatty liver”.
The claims broadly encompass any fusion protein comprising any fragment of flagellin or any variant of flagellin and an Fc region of an immunoglobulin for prevention or treatment of fatty liver or metabolic syndrome in any subject. The claims do not require that a flagellin fragment or any variant of flagellin possess any particular feature or structure that may treat a metabolic disorder fatty liver disease.
The specification at pg.22, discloses making a fusion protein wherein Bacillus subtilis flagellin (Bsflagellin) (SEQ ID NO: 11) is conjugated with an Fc (SEQ ID NO: 7) with a linker(GGGGS of SEQ ID NO:8). The specification at pg. 25 discloses that the administration of mIgG1-Fc2-Bsflagellin fusion protein to a mice group fed with high fat diet improves or metabolic syndrome. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. Some of the factual considerations that are weighed when determining a written description include the level of skill and knowledge in the art, the disclosure of complete or partial structures, the disclosure of physical and or chemical properties, adequate disclosure of the functional characteristics, the correlation between structure and function, and disclosure of methods of making.
In the instant case, the specification at pg.22, discloses making a fusion protein wherein Bacillus subtilis flagellin (Bsflagellin) (SEQ ID NO: 11) is conjugated with an Fc (SEQ ID NO: 7) with a linker(GGGGS of SEQ ID NO:8). The specification at pg. 25 discloses that the administration of mIgG1-Fc2-Bsflagellin fusion protein to a mice group fed with high fat diet improves or metabolic syndrome. Cuadros et al (Infection and Immunity 2004, 72: 2810-2816) teach that flagellin fusion proteins to enhance immunity by flagellin activation of antigen presenting cells (APC). KR 200800774556A (IDS) teaches that a fusion protein comprising PAS-flagellin improves Toll-Like Receptor 5 (TLR5) activity. The specification does not describe any flagellin fragment of 5, 10, 20, 50, or even 75 amino acids length or any flagellin variant having 30%, 40%, 50%, 90% or 95% when conjugated with an Fc can treat any metabolic disorder or fatty liver disease. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1 "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
Vas-Cath Inc. V. Mahurka, 19 USPQ2d 1111, states 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, for purposes of the written description inquiry, is whatever is now claimed (see page 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 at page 1116).
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 of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B (1), the court states an adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.
As discussed above, the skilled artisan cannot envision the detailed genus of “any fragment or any variant of flagellin fusion with an Fc can treat or prevent any metabolic disorder or fatty liver disease in a subject” and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of making a mutation. The compound itself is required. See Fiers v.Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen v.Baird, 30 Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 148 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.
Therefore, only a composition comprising flagellin polypeptide of SEQ ID NO: 11 fused with an Fc, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph.
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).
Claim Rejections - 35 USC § 112-scope of enablement
Claims 1-19 and 21 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 non-alcoholic fatty liver disease or metabolic syndrome comprising a composition comprising flagellin of amino acid sequence of SEQ ID NO: 11 conjugated with an Fc, does not reasonably provide enablement for a method of preventing any metabolic syndrome or fatty liver disease comprising administering any fragment of a flagellin or any variant of flagellin conjugate with an Fc to a subject in need thereof. 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/or use the invention commensurate in scope with these claims.
In In re Wands, 8USPQ2d, 1400 (CAFC 1988) page 1404, the factors to be considered in determining whether a disclosure would require undue experimentation include: (1) Nature of the invention, (2) the state of the prior art, (3) the predictability or lack thereof in the art, (4) the amount of direction or guidance present, (5) the presence or absence of working examples, (6) the breath of the claims, (7) the quantity of experimentation needed, (8) relative skill of those in the art.
The instant disclosure fails to meet the enablement requirement for the following reasons:
Claims 1-19 and 21 are broadly drawn to a method for prevention, treatment or use of a fusion protein for non-alcoholic fatty liver diver diseases or metabolic syndrome comprising a flagellin fragment, any variant of flagellin conjugate with an Fc to a subject.
The state of the prior art and the predictability or lack thereof in the art:
With regards to the prevention or treatment of non-alcoholic fatty liver disease or metabolic disorder by administering a composition comprising flagellin, a fragment or variant thereof conjugated with an Fc, the specification does not disclose sufficient guidance or objective evidence that a fusion of flagellin fragment or flagellin variant or flagellin would predictably prevent non-alcoholic fatty liver or metabolic disorder.
Cuadros et al (Infection and Immunity 2004, 72: 2810-2816) teach that flagellin fusion proteins to enhance immunity by flagellin activation of antigen presenting cells (APC). KR 200800774556A (IDS) teaches that a fusion protein comprising PAS-flagellin improves Toll-Like Receptor 5 (TLR5) activity. The problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinants to ascertain functional aspects of the protein is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein’s sequence where such amino acid substitutions can be made with a reasonable success are limited. Certain positions in the sequence are critical to the protein’s structure/function relationship, such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These regions can tolerate only relatively conservative substitutions or no substitution (Bowie et al., 1990, Science 247: 1306-1310, page. 1306, column 2, paragraph2; Wells, 1990, Biochemistry 29:8509-8517). The N-terminal and C-terminal of flagellin protein are conserved but the claims require a composition, pharmaceutical composition or food comprising a fusion protein having any fragment of flagellin or any variant of flagellin fused with an Fc that can treat or prevent any metabolic disorder or fatty liver disorder. Therefore, it would require a large amount of experimentation to make millions of variants including substitutions, deletions or insertions in a flagellin polypeptide or to generate millions of fragment of flagellin and the prepare their conjugates with an Fc that can prevent or even treat metabolic syndrome or non-alcoholic fatty liver disease.
The amount of direction and guidance present and the presence or absence of working examples: Given the teachings of unpredictability found in the art, detailed teachings are required to be present in the disclosure in order to enable the skilled artisan to practice the invention commensurate in scope with the claims. These teachings are absent. The specification discloses in general teaches that a fusion protein comprising flagellin polypeptide of SEQ ID NO: 11 when conjugated with an Fc via a linker peptide GGGGS can treat non-alcoholic fatty liver while having no effect on body weight. The specification does not provide any guidance that a fragment of 5, 10, 30, 40, 50 or 75 amino acids in length can prevent or even treat any metabolic syndrome such as obesity, insulin resistance, fatty liver, hyperlipidemia or hypertension. The specification does not provide any guidance that any variant of flagellin for example, a variant having 10%, 20%m 50%, 60%, 70%, 70%,80%, 90% or more variation from flagellin sequence (SEQ ID NO: 11) when conjugated with an Fc can treat any metabolic syndrome. Therefore, it is unpredictable how one of the skill in the art can practice the instantly claimed invention.
The breadth of the claims and the quantity of experimentation needed: Because the claims encompass a method of treating or preventing metabolic disease or non-alcoholic disease comprising administering any variant of flagellin conjugated with an Fc or any fragment of flagellin conjugated with an Fc in a subject, the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to same, the state of the prior art which establishes the unpredictability about administering any fragments or variants of flagellin conjugated with an Fc for preventing or treating of a metabolic disorder, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Conclusion
No claim is allowed.
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/GYAN CHANDRA/Primary Examiner, Art Unit 1674