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 present Application, filed April 13, 2023, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/IL2021/051222, filed October 13, 2021, which claims priority to U.S. Provisional Patent Application No. 63/091,968, filed October 15, 2020.
Status of the Claims
Claims 1-17 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 16, 2023 is acknowledged.
Claim Rejections - 35 USC § 112
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 1-2 and 4-17 are indefinite:
Claims 1-2 and 4-17 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 1 is indefinite for reciting, “a therapeutically effective amount of a Rho Kinase inhibitor, or an inhibitor of a downstream effector thereof,” because a person of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. In particular, one could not reasonably determine what constitutes a downstream effector of a Rho Kinase or know what constitute inhibitors of such downstream effectors. Rho kinases have many substrates, including, but not limited to, myosin light chain (MLC), myosin phosphatase target subunit (MYPT)-1, ezrin/radixin/moesin family, adducin, phosphatase and tensin homolog (pten), endothelial NO synthase (eNOS), Tau, and LIM-kinase. Most of these have their own branching chains of downstream effectors (see, for example, the non-patent publication, RhoA/Rho-Kinase in the Cardiovascular System, Circulation Res., 118, pgs. 352-366 (2016) by Shimokawa et al.). For example, pten alone is involved in multiple signal transduction pathways relating to apoptosis/cell survival (see, for example, the non-patent publication, The Multiple Roles of PTEN in Tumor Suppression, Cell, 100, pgs. 387-390 (2000) by Di Cristofano et al). Given the variety of molecular interactions and signaling cascades that are “downstream” of Rho kinases, and the absence of limitation of how far downstream of rho kinase such effectors can be, to be effectors of instant claim 1, this feature is indefinite. Claims 2 and 4-17 are indefinite for depending from claim 1 without curing this indefiniteness.
Claim 4 is further indefinite for reciting “wherein said SRSF2 mutation is a point mutation a deletion, a frameshift mutation, a nonsense mutation and a missense mutation” because a person of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. The SRSF2 mutation cannot simultaneously be each of those types of limitation, because some of them are mutually exclusive categories, e.g. a missense mutation cannot be a nonsense mutation. It is assumed that this recitation is intended to be a Markush group (i.e. the SRSF2 mutation is selected from the group consisting of a point mutation, etc.) but the recitation is not properly written as a Markush group.
Claims 12-17 recite the limitation "the ROCK inhibitor" in the first line of each claim. There is insufficient antecedent basis for this limitation in the claim. In particular, claim 1, from which these claims depend, recites “a Rho Kinase inhibitor,” and does not provide an acronym or abbreviation for this term. The ROCK inhibitor of the dependent claims is presumed to refer to the Rho Kinase inhibitor of claim 1, but in order to have proper antecedent basis, the element in the dependent claims must have verbatim support in the claim from which they depend.
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 1-4 and 6-17 fail to comply with the written description requirement:
Claims 1-4 and 6-17 are rejected under 35 U.S.C. § 112, first paragraph, as failing to comply with the written description requirement. The claims 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 inventors, at the time the application was filed, had possession of the claimed invention.
Specifically, Applicant does not have written description support for a method of treating or preventing a myeloid malignancy in a subject harboring a mutation in SRSF2 comprising administering to the subject a therapeutically effective amount of a Rho Kinase inhibitor upon identification of SRSF2 mutation, when the mutation is other than a mutation involving Pro95 of the SRSF2 gene. As discussed further below, the examples of the instant specification only involve, and demonstrate enhanced efficacy of Rho Kinase inhibition, in subjects having mutations involving Pro95. Furthermore, the art indicates that, while many other mutations of SRSF2 are known, there is no indication that mutations not involving Pro95 would have any connection to myeloid malignancy or would be indicative of particular suitability for treatment by Rho Kinase inhibition, as has been shown in the instant specification for mutations involving Pro95. As such, the present claims other than claim 5 lack sufficient written description.
The written description requirement is distinct from the enablement requirement; as was first pointed out by the court in In re Ruschig, 3 79 F .2d 990, 154 USPQ 118 (CCP A 1967), and clarified in Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111 (Fed. Cir. 1991). The issue of whether the claimed subject matter is adequately supported/described by the specification, is a question of fact. Id. at 1563, 19 USPQ2d at 1116.
When considering whether the claimed subject matter complies with the written description requirement, Applicants' disclosure should be read in light of the knowledge possessed by those skilled in the art.
"[T]he disclosure in question must be read in light of the knowledge possessed by those skilled in the art, and that knowledge can be established by affidavits of fact composed by an expert, and by referencing to patents and publications available to the public ... "
In re Lange, 644 F.2d 856, 863, 209 USPQ 288, 294. See also, In re Alton, 76 F.3d 1168, 37 USPQ2d 1578 (Fed. Cir. 1996).
Applicants enjoy the presumption that their patent application is valid and all statements contained therein are accurate; it is the PTO's burden to demonstrate why any of Applicants claims should be rejected or why any of Applicant's statements should be doubted.
"it is incumbent upon the Patent Office, whenever a rejection ... is made, to explain why it doubts the truth or accuracy of any statement in a supporting disclosure and to back up assertions of its own with acceptable evidence or reasoning which is inconsistent with the contested statement. Otherwise, there would be no need for the applicant to go to the trouble and expense of supporting his presumptively accurate disclosure."
In re Marzocchi, 439 F.2d 220, 224, 169 USPQ 367, 370. If successful in presenting such evidence and argument, the burden then shifts to the Applicant to provide evidence that would convince one to the contrary.
The Invention in General
Applicant’s invention is directed to methods of treating myeloid malignancies, such as acute myeloid leukemia. The methods involve determining whether a potential subject has a mutation in the gene encoding Serine/arginine-rich splicing factor 2 (SRSF2) and, if the subject does have such a mutation, administering an inhibitor or a Rho Kinase or a downstream effector of Rho Kinase (i.e. a protein involved in a signaling cascade downstream of a Rho Kinase).
The Claimed Invention
The claimed invention is directed to a method of treating or preventing a myeloid malignancy in a subject harboring a mutation in SRSF2 comprising: (a) analyzing in a sample of the subject for the presence of an SRSF2 mutation; and (b) administering to the subject a therapeutically effective amount of a Rho Kinase inhibitor, or an inhibitor of a downstream effector thereof, upon identification of SRSF2 mutation, thereby treating or preventing the myeloid malignancy.
Various dependent claims specify downstream effectors (claim 3), details of the SRSF2 mutations (claims 4-5), specific myeloid malignancies (claims 6-8), details regarding sample analysis for SRSF2 mutations (claims 9-11), and details regarding the Rho Kinase inhibitor (claims 12-17).
The claimed method is understood as utilizing the sample analysis as a determining factor in whether to proceed with administration of the Rho Kinase inhibitor – i.e. suitability of Rho Kinase inhibitor treatment is indicated if an SRSF2 mutation is present, and is not indicated if an SRSF2 mutation is not present.
The Supporting Disclosure
Applicants' supporting disclosure states that SRSF2 mutations are common among people who have myeloid malignancies. Cited references describe Rho kinases, treatment of myeloid malignancies and, to some extent, the overlap of the two, but do not deal with mutations of SRSF2 in myeloid malignancies. The disclosure notes prior art teaching the potential general utility of Rho kinase inhibitors in treating acute myeloid leukemia (Pession, cited inter alia at pg. 5, line 15 of the present disclosure), and notes that the present invention is based on a chemical library search of compounds that specifically target myeloid malignant cells harboring SRSF2 mutations (pg. 5).
The disclosure indicates that inhibitors of Rho kinases were discovered, as a result of this search, to be effective in targeting such cells. As such, the disclosure describes the method for treating a myeloid malignancy, in terms substantial the same as the claim language (pg. 5). The disclosure then defines various terms relative the claims and describes various embodiments and details relevant to the dependent claims, as described above (pgs. 6-10)
The disclosure then describes various materials and sub-methods that can be used with the method of the invention, e.g. for obtaining a sample from a subject or analyzing the sample for the presence of an SRSF2 mutation (pgs. 10-43) and additional definitions, particularly relating to pharmaceutical compositions of Rho kinase inhibitors and/or LIMK2 inhibitors (LIMK2 being a preferred downstream effector, as recited in instant claim 2).
Finally, the disclosure describes the Examples (pg. 51-56), beginning with materials and methods used (pgs. 51-54) and continuing with the observed Results (pgs. 54-56). In particular, the disclosure indicates that isogenic models of P95H mutant SRSF2 were created in hematopoietic cell lines with CRISPR technology. Five different cell lines were used, but all were transformed with P95H SRSF2. The disclosure does not indicate that any mutations of SRSF2 that do not involve Pro95 were evaluated in the chemical library screen to identify compounds having enhanced effectiveness against SRSF2 mutant myeloid malignancies. The screening results indicate that several Rho kinase inhibitors – especially RKI-1447 – were found to have a greater efficacy in the constructed SRSF2-mutant hematopoietic cells than in WT SRSF2 hematopoietic cells. To reiterate, only SRSF2 mutants carrying the P95H mutation appear to have been evaluated
The State of the Art
A number of references establish that many mutants of SRSF2 are known, but do not have any known association with myeloid malignancies.
For example, the non-patent publication, Catalogue of Somatic Mutations in Cancer, an online database of mutations in various cancers and tissues, obtained at the url cancer.sanger.ac.uk/cosmic/gene/analysis?ln=SRSF2 (hereinafter, “COSMIC_SRSF2”), lists at least 298 genetic mutations of the SRSF2 gene that have been observed in cancerous tissues, the listing of mutations curated from some 566 references. A summary, along with a listing of 298 mutations observed at varying frequencies in 1894 tissue samples is appended to this document. While the most common mutations involve amino acid point mutations at Pro95, followed by deletions involving Pro95, there are also many mutations at other positions, albeit at lower frequency. Moreover, it is virtually certain that at least some of these mutations have no functional effect on cancer generally, including myeloid malignancies, as a number of silent mutations are observed (e.g. the 2nd and 4th mutations listed on pg. 7 of the appended COSMIC_SRSF2 summary are silent mutations). Given that silent mutations are found in cancerous tissues, it is likely that other clinically insignificant mutations exist and may be found in cancers, including in myeloid malignancies.
Furthermore, a number of references indicate that mutations involving Pro95 are known to be uniquely clinically relevant to myeloid malignancies, with other mutations being of no known clinical importance. For example, the non-patent publication, SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes, Haematologica, 99, pgs. 830-835 (2014) by Hanssens et al. (hereinafter, “Hanssens”) teaches that mutations at Pro95 of SRSF2 are an oncogenic “hotspot,” being the most frequent of all gene mutations in a study of mastocytosis mutations, and the only SRSF2 mutations observed (pg. 831, right column, SRSF2P95 hotspot mutation is highly correlated with advanced forms of mastocytosis).
Similarly, the non-patent publication, SRSF2 mutations in myelodysplasia/myeloproliferative neoplasms, Biomarker Res., 6, article 29, pgs. 1-7 (2018) by Aujla et al. (hereinafter, “Aujla”) teaches that Pro95 mutations are uniquely significant in the development of cancer and in particular myeloid malignancies. For example, Aujla teaches that:
While loss of SRSF2 led to decreased survival, mutant SRSF2 (SRSF2-mut) expression was associated with oncogenesis. Direct association of SRSF2 in development of myelodysplasia was demonstrated in SRSF2-P95H mutant mice [40]. P95H is the most common mutation site in the SRSF2 gene [41,42,43,44,45] and its proximity to RRM site of SRSF2 might play a role in altering RNA binding abilities [38] [46]. Heterozygous P95H mutant and homozygous SRSF2 deleted bone marrow mononuclear cells led to development of significant leukopenia and anemia in lethally irradiated recipient mice. However, only P95H mutated mice developed macrocytic RBCs and had normal bone marrow cellularity in contrast to bone marrow aplasia seen with homozygous SRSF2 deletion. Peripheral erythroid and myeloid dysplasia was also seen only with P95H mutant mice [40]. These findings correlate with MDS findings in humans.
-Aujla, pg. 2, left column, second paragraph
Thus the art indicates the unique importance of mutations involving Pro95 of SRSF2, among other existing SRSF2 mutations, in the development of myeloid malignancies. Furthermore, the art indicates that other mutations, not known to be clinically relevant, may be found in cancers, albeit at lower frequency.
Summary of Written Description Rejection
As discussed above, the present specification only discloses generating and detecting mutations involving Pro95 (particularly P95H) in subjects, and only demonstrates enhanced efficacy of Rho kinase inhibitors in treating myeloid malignancies having this mutation. There is no evidence that subjects harboring mutations of SRSF2, other than the P95H mutation, would experience any improvement in efficacy from Rho kinase treatment relative to a subject having WT SRSF2. Furthermore, the art of record indicates that mutations of SRSF2 involving Pro95 are a known oncogenic hotspot, and that other mutations, which may be present, are of little-to-no known clinical relevance in the progression of myeloid malignancies.
In view of these findings, claims 1-4 and 6-17, which claim a method for treating myeloid malignancy in which detection of any mutation in SRSF2 is an indicator for treatment with a Rho kinase inhibitor, fail to satisfy the written description requirement.
Potentially Allowable Subject Matter
Claim 5 recites subject matter that, if the indefiniteness arising from its dependency from claim 1 were overcome and if rewritten in independent form while otherwise retaining the limitations of claim 1, would be allowable in view of the current record.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629