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
This Application is a 371 of PCT/US2023/027083 filed on 07/07/2023, which has a PRO 63/389,497 filed on 07/15/2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed 5/29/25 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
The rejections are as below:
Claim Rejections –
35 USC § 112 Notice of Pre-AlA or AIA Status
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 1-19, 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 treatment of mice administered EED A395 IN 100MG/KG or 300MG/KG twice per week or MAK683 in 50 mg/kg or 20 mg/kg or 10 mg/kg or 5 mg/kg s.c. twice per week improved bone formation in OI. 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 are drawn to a method for promoting bone growth in a mammal having a bone disorder, wherein said method comprises administering an inhibitor of an embryonic ectoderm development (EED) polypeptide activity to said mammal, wherein bone growth increases within said mammal following said administering. The instant specification fails to provide information that would allow the skilled artisan to practice the promoting nay bone growth disorder and any inhibitor or EED.
[In re Sichert, 196 USPQ 209 (CCPA 1977)]
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative
skill level
The invention relates to a method for promoting bone growth in a mammal having a bone disorder, wherein said method comprises administering an inhibitor of an embryonic ectoderm development (EED) polypeptide activity to said mammal, wherein bone growth increases within said mammal following said administering.
The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, the examiner cites the fact that while Applicant demonstrated the use of only 2 EED inhibitors for treatment of OI, nowhere in the specification did applicant demonstrate the use of ALL EED inhibitors to promote bone growth. Further, the predictability of treating bone growth is relatively low given that the various types of conditions have different causative agents, involve different cellular mechanisms, and consequently, differ in treatment protocol. Thus, given that applicant has failed to demonstrate a method for promoting bone growth in a mammal having a bone disorder, wherein said method comprises administering an inhibitor of an embryonic ectoderm development (EED) polypeptide activity to said mammal, wherein bone growth increases within said mammal following said administering, the examiner maintains that applicant has not enabled the breadth of the claims.
2 The breadth of the claims
The claims are thus very broad insofar as they recite the “a method for promoting bone growth in a mammal having a bone disorder, wherein said method comprises administering an inhibitor of an embryonic ectoderm development (EED) polypeptide activity to said mammal, wherein bone growth increases within said mammal following said administering. While such “treatment” might theoretically be possible for treating OI utilizing A395 AND MAK683, as a practical matter it is nearly impossible to achieve method for promoting bone growth in a mammal having a bone disorder, wherein said method comprises administering with ALL inhibitors of an embryonic ectoderm development (EED) polypeptide activity to said mammal, wherein bone growth increases within said mammal following said administering.
3. The amount of direction or quidance provided and the presence or absence of working examples
The specification provides no direction or guidance for the use of ALL inhibitors of an embryonic ectoderm development (EED) polypeptide activity in promoting bone growth. No reasonably specific guidance is provided concerning useful therapeutic protocols for the use of ALL inhibitors of an embryonic ectoderm development (EED) polypeptide activity in promoting bone growth, other than example 2-4. The latter is corroborated by the working examples on pages 19-27. Examiner points to final paragraphs in examples 5-6 wherein:
The administered inhibitor(s) can increase bone growth in the human by at least 5 percent as measured by BMD (e.g., as compared to a comparable human that was not administered the inhibitor).
Applicant clearly does not incorporate results of the treatment regimen claimed.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that every instantly claimed inhibitors of an embryonic ectoderm development (EED) polypeptide activity could be predictably used for promoting bone growth as inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dudakovic et al. (Enhancer of zeste homolog 2 (Ezh2) controls bone formation and cell cycle progression during osteogenesis in mice. J Biol Chem. 2018 Aug 17;293(33):12894-12907. doi: 10.1074/jbc.RA118.002983. Epub 2018 Jun 13. PMID: 29899112; PMCID: PMC6102149 -- IDS) in view of He et al. (The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol. 2017 Apr;13(4):389-395. doi: 10.1038/nchembio.2306. Epub 2017 Jan 30. Erratum in: Nat Chem Biol. 2017 Jul 18;13(8):922. doi: 10.1038/nchembio0817-922b. PMID: 28135237).
Dudakovic et al. teaches the biological role of Ezh2 is suppressing osteogenic differentiation, and it has a positive function in early stages of bone formation by supporting pre-osteoblast proliferation. The reference shows EZH1 and EZH2 require an intact Polycomb Repressive Complex 2 (PRC2) to function, their baseline role facilitates the early mesenchymal lineage development and suppresses the late osteogenic lineage differentiation commitment of stem cells to functional osteoblast or osteoprogenitor cells, and serves a bifunctional role during bone formation.(Reads on treatment of OI or a genetic bone disorder or osteoporosis in adult and juvenile). Further, PRC2‐EZH2 complex plays histone H3K27me3 methyltransferase activity in determining stem cells differentiation, with the interaction of ncRNAs, histone acetyltransferases (HATs), histone demethylase (HDMs), and DNA methyltransferase (DNMs), etc. PRC1‐dependent H2AK119ub1 provides recognition binding sites and promotes further deposition of H3K27me3 in PRC2‐EZH2 loci. With HDMs interaction, H3K4me3 also be modified in the target genes of PRC2‐EZH2. PRC2‐EZH2 regulates the key targets such as DLX5, OSX, RUNX2, and β‐catenin causing the osteogenic differentiation and bone formation.
The reference fails to specify an inhibitor of EED polypeptide activity.
He et al. teaches polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. The data shows s.c. delivery of A-395 at 300 mg/kg two times per week for 5 weeks.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Dudakovic et al. AND He et al. to promote bone growth. The motivation comes from the teaching in Dudakovic et al. that Ezh2/PRC2 suppresses late osteogenic differentiation and supports early proliferation. Further Ezh2/PRC2 modulates key genes like DLX5, OSX, RUNX2, and βbeta, 𝛽 -catenin via H3K27me3, therefore, having a bifunctional role. Additionally, He et al. teaches EED binds H3K27me3 to activate PRC2 catalytic function and A-395 binds the EED pocket preventing catalytic activity of PRC2. A skilled artisan would have had reasonable expectation of successfully promoting functional osteoblast differentiation and bone growth. Additionally, since the general conditions of the claim are taught in the prior art, discovering optimum or workable dosage regimen, that is administering the inhibitor once per day to about once per month, in amounts of about 5 mg/kg to about 300 mg/kg involves only routine skill in the art (In re Aller).
Claim 21 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dudakovic et al. (Enhancer of zeste homolog 2 (Ezh2) controls bone formation and cell cycle progression during osteogenesis in mice. J Biol Chem. 2018 Aug 17;293(33):12894-12907. doi: 10.1074/jbc.RA118.002983. Epub 2018 Jun 13. PMID: 29899112; PMCID: PMC6102149.) in view of He et al. (The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol. 2017 Apr;13(4):389-395. doi: 10.1038/nchembio.2306. Epub 2017 Jan 30. Erratum in: Nat Chem Biol. 2017 Jul 18;13(8):922. doi: 10.1038/nchembio0817-922b. PMID: 28135237) as applied to claims 1-19 above, and further in view of Ascher et al. (Fulcrum Therapeutics Announces Preclinical Proof-of-Concept Data for FTX-6058 at the Virtual 14th Annual Sickle Cell Disease Research & Educational Symposium and 43rd National Sickle Cell Disease Scientific Meeting. September 25, 2020).
Dudakovic et al. and He et al. are discussed above.
Dudakovic et al. and He et al. fail to teach FTX-6058.
Ascher et al. FTX-6058, a highly potent small molecule inhibitor of Embryonic Ectoderm Development (EED).
It would have been obvious to one of ordinary skill in the art to use FTX-6058 in the formulation. The motivation comes from the teaching in Ascher et al. that FTX-6058, a highly potent small molecule inhibitor of Embryonic Ectoderm Development (EED). A skilled artisan would have had reasonable expectation of successfully promoting functional osteoblast differentiation and bone growth with an EED inhibitor such as FTX-6058.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Layla Soroush whose telephone number is (571)272-5008. The examiner can normally be reached on Monday through Friday from 8:30 a.m. to 5:00 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, James Henry Alstrum-Acevedo, can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LAYLA SOROUSH/ Primary Examiner, Art Unit 1622
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