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 .
Applicant’s election without traverse of group I and the species:DHRS7B, DNA targeting system, a fusion protein comprising nuclease-deficient S. pyogenes Cas9 and KRAB, SEQ ID NO:18, SEQ ID NO: 21, transcription repression activity, SEQ ID NO: 53 and SEQ ID NO: 69, PWS Type 1 large deletion, and SNRPN in the reply filed on 4/16/26 is acknowledged.
It is noted that SEQ ID NOs: 53-56 have been examined because they are minimal species directed to the same target, DHRS7B.
Claims 4, 12, 15, 22, and 28-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/16/26.
Claim Objections
Claims 1-3, 8, 11, 16, 17, 19, 21, 23, 24, and 27 are objected to because of the following informalities: The claims recite abbreviations for genes. The claims are required to recite the full name with the abbreviation in parentheses for the first recitation of the abbreviation (i.e. dehydrogenase/reductase 7B (DHRS7B)). Appropriate correction is required.
Improper Markush Rejection
Claims 1-3, 8, 11, 16, 17, 19, 21, 23, 24, and 27 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims are directed to a genus of genes that each have a different sequence and activity. Inhibitors of each of the genes would have different structures or sequences and different activities.
Each gene contains a unique sequence of DNA that encodes for a specific protein and is located at a different position on the human chromosomes.
Claim 4 is withdrawn because it is directed to non-elected subject matter but would be subject to this rejection because each of the agents have different structures and act via different mechanisms.
With regards to claim 8, zinc fingers are engineered chimeric proteins combining a zinc finger DNA-binding domain (each recognizing a 3-base triplet) with a FokI nuclease domain that cuts DNA. Two ZFN subunits bind adjacent DNA strands, dimerize, and create a double-strand break (DSB) at the target site. The cell repairs the break via non-homologous end joining (NHEJ) or homology-directed repair (HDR), enabling gene knockout or insertion; whereas CRISPR/Cas9 systems use a guide RNA (gRNA) to direct the Cas9 nuclease to a complementary DNA sequence. The gRNA is easy to design for any target, and Cas9 creates a DSB at that site.
The TALE is composed of repeats of 33-35 amino acids, each repeat recognizing one specific DNA base, wherein DNA DNA sequence specificity is conferred by repeat-variable di-residues (RVDs). DNA-binding fusion proteins are artificial constructs where a DNA-binding domain (DBD) is genetically fused to another functional domain (FD).
The agents do not have sufficiently similar structures to provide the same function because each has a structure that dictates that it acts via a different mechanism. Therefore, the members of the Markush group lack any common substantial structural feature that provides a common use, and the group of alternatives is an improper Markush group.
Additionally, claims 11 and 19 recite a genus of polypeptide domain elements that have different sequences and activities. One cannot be substituted for another with expectation of identical activity. For example, KRAB is a short protein domain (~25–30 amino acids) that recruits co-repressor complexes, such as KAP1 (KRAB-associated protein 1), which in turn recruit histone methyltransferases (e.g., SETDB1) and histone deacetylases (HDACs); whereas MeCP2 binds specifically to methylated CpG dinucleotides and recruits co-repressor complexes (e.g., NCoR/SMRT, HDACs) to repress transcription.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled:
(A) All alternatives have a common property or activity; and
(B) (1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or
(B) (2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together.
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific inhibitor is dependent upon the specific sequence of nucleotides and/or structure, each differing based upon completely different target gene sequences. There is no expectation that any one of the genes as claimed can be substituted for any of the other with a completely different sequence with the expectation of the same activity.
As set forth in MPEP2117, “Note that where a Markush group includes only materials from a recognized scientific class of equivalent materials or from an art-recognized class, "the mere existence of such a group in an application tend[s] to prove the equivalence of its members and when one of them [is] anticipated the group [is] therefore rendered unpatentable, in the absence of some convincing evidence of some degree of non-equivalency of one or more of the remaining members." In re Ruff, 256 F.2d 590, 598-99, 118 USPQ 340, 348 (CCPA 1958)("[A]ctual equivalence is not enough to justify refusal of a patent on one member of a group when another member is in the prior art. The equivalence must be disclosed in the prior art or be obvious within the terms of Section 103." Id. at 599, 118 USPQ at 348).”
In the instant case, art against any one inhibitor for any one gene would not be evidence against any of the remaining members that have completely different sequences and/or structures and do not have identical activity.
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 23, 24, and 27 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 23 and 27 recite the limitation "at least one component thereof" in the composition of claim 1. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite components.
It is not clear or definite what is meant by “at least one component” of the composition of claim 1 because the composition of claim 1 does not recite multiple components.
Additionally, claim 23 recites a polynucleotide encoding the composition or any component thereof of claim 1. It is not clear how the polynucleotide would encode the entire composition or any component rather than encode a specific nucleic acid.
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 1-3, 8, 11, 16, 17, 19, 21, 23, 24, and 27 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.
Claim 1 recites “a PWS-like disorder”, which is a genus that has not been adequately described in the specification. The specification discloses PWS but does not disclose representative species of PWS-like disorders that are representative of the entire claimed genus. Without further description of the genus, one would not be able to readily envision which disorders are “PWS-like” and which disorders are necessarily excluded from the recited genus. For example, PWS is characterized by hunger. Therefore, any hunger disorder or disorder with any association to hunger would meet the instant limitation of being “PWS-like”.
Additionally, the claims recite that the composition comprises an inhibitor of DHRS7B and that the composition reduces the expression of DHRS7B or reduces an activity of a protein encoded by DHRS7B. The specification does not adequately describe the structure required for the function. Without further description of the structure required for the function, one would not be able to readily recognize which compounds necessarily have the structure required to function as an inhibitor of DHRS7B and to reduce the expression of DHRS7B or reduce an activity of a protein encoded by DHRS7B. The inhibitor is not required to have any specific structural relationship with any specific DHRS7B sequence, but rather can be specific to another target and have the secondary effect of inhibiting DHRS7B, for example, which is a genus of agents that has not been adequately described in the specification.
The specification discloses gRNAs that are identical to a gRNA targeted sequence in a specific DHRS7B target sequence (pages 55 and 81 of specification), which is not representative of the entire claimed genus of any compound that is capable of inhibiting DHRS7B on any level.
Claim 8 requires for the inhibitor to comprise a DNA binding fusion protein that targets DHRS7B, wherein the fusion protein comprises a polypeptide domain having transcription repression activity. The specification does not adequately describe the structure required for the DNA binding fusion protein polypeptide domain to have the function of DHRS7B transcription repression activity. The claims do not require any specific structural relationship between the DNA binding fusion protein and a specific DHRS7B sequence to result in the required function.
Claim 23 is directed to a polynucleotide encoding the composition of claim 1, which is interpreted as a polynucleotide encoding the inhibitor. The specification does not adequately describe which polynucleotides encode inhibitors of DHRS7B.
Additionally, the claims do not recite a specific DHRS7B nucleotide sequence by SEQ ID NO, but rather refer to the broad genus of DHRS7B sequences.
The claims encompass a method of introducing any type of DHRS7B inhibitor to inhibit the expression of any DHRS7B sequence, as well as encompass any DHRS7B homolog or allele from any species known or yet to be discovered of DHRS7B, as well as DNA genomic fragments, spliced variants or fragment that retains DHRS7B-like activity.
Furthermore, although the specification discloses gRNAs that are specific for a DHRS7B sequence, the specification does not describe such agents directed to any other species of DHRS7B to describe the instantly claimed genus of any DHRS7B. Each of the instantly disclosed agents is targeted to a single sequence, although the claims are drawn to any DHRS7B. One of ordinary skill in the art could not make such agents to any DHRS7B without knowledge of the sequence and knowledge of the types of inhibitory molecules. Given the breadth of sequences embraced in the instantly claimed genus, one could not envision the member agents that target such a broad genus.
From a review of DHRS7B, it appears that it is also known as PexRAP or retSDR4. Without further description of the sequence, one would not be able to readily envision what sequence the instant claims are limited to.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
To achieve the desired function, with respect to siRNAs, a single species of possible inhibitors, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for each of the recited genuses that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3 and 27 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Honsho et al. (Frontiers in Cell and Developmental Biology, 9/2020, 8, 855, 1-16).
Honsho et al. teach a composition comprising siRNA targeting DHRS7B with resultant inhibition of DHRS7B expression (pages 12-13) (instant claims 1-3 and 27). The intended use language of the preamble of instant claim 1 does not introduce any specific structural limitation for the composition claim.
Honsho et al. teach: Upon transfecting siRNA against DHRS7b, synthesis of PlsEtn and phosphatidylethanolamine (PtdEtn) was reduced about 40% of those in mock-treated cells (Figures 1C,D) (page 2).
Since Honsho et al. teaches a composition meeting each of the instant structural limitations, the composition would necessarily achieve the recited outcome, absent evidence to the contrary. As stated in the MPEP (see MPEP 2112), something that is old does not become patentable upon the discovery of a new property.
Therefore, the instant invention is anticipated by Honsho et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 23 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Honsho et al. (Frontiers in Cell and Developmental Biology, 9/2020, 8, 855, 1-16) as applied to claims 1-3 and 27 above, and further in view of Amarzguioui et al. (FEBS Letters 579 (2005) 5974–5981).
Honsho et al. does not teach a polynucleotide encoding the inhibitor or a vector comprising the polynucleotide.
However, this was a routine manner to deliver and express siRNA, as evidenced by Amarzguioui et al.
Amarzguioui et al. teach expression of shRNAs or siRNAs in mammalian cells can be achieved via transcription from either Pol II or Pol III promoters. Amarzguioui et al. teach strategies for inducible shRNA expression and the various viral vectors that can be used to transduce shRNA genes into a variety of cells and tissues in vivo (abstract).
It would have been obvious to deliver the siRNA of Honsho et al. via the vector comprising a sequence encoding the siRNA as a matter of design choice with the expectation of inducing expression intracellularly (instant claims 23 and 24).
Additionally, since Honsho et al. teach that: Upon transfecting siRNA against DHRS7b, synthesis of PlsEtn and phosphatidylethanolamine (PtdEtn) was reduced about 40% of those in mock-treated cells (Figures 1C,D) (page 2); it would have been obvious to deliver the composition of Honsho et al. in vivo when it is beneficial to inhibit plasminogen.
Claim(s) 8, 11, 16, 17, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Honsho et al. (Frontiers in Cell and Developmental Biology, 9/2020, 8, 855, 1-16) as applied to claims 1-3 and 27 above, and further in view of Yeo et al. (Nature Methods, 15, 2018, 611–616), and Joung et al. (US 2014/0377868 A1).
Honsho et al. does not teach incorporation of a DNA binding fusion protein that targets DHRS7B comprising a nuclease-deficient S. pyogenes Cas9 and KRAB (instant claims 8, 11, 17, and 19).
However, Yeo et al. teach that the RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor and that they describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB–MeCP2, to nuclease-dead Cas9. Yeo et al. teach that they demonstrate the system’s superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits (abstract).
Therefore, it would have been obvious to utilize this system instead of the siRNA of Honsho et al. to target and inhibit DHRS7B as a matter of design choice because each were known to be transcriptional repressors. One would reasonably expect the superior silencing taught by Yeo et al. when targeting DHRS7B.
It would have been obvious for the Cas9 sequence to comprise instant SEQ ID NO: 21 (instant claim 16) because it is a fragment of the known Cas9 sequence, as taught by Joung et al. Joung et al. teach a Cas9 sequence comprising the instant sequence for RNA-guided targeting to specific genomic loci (see SEQ ID NO: 3 comprising instant SEQ ID NO: 21 at nucleotides 1-1368).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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