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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/04/2025 has been entered.
Claim Status
1. The amendment filed 09/04/2025 has been entered. Claims 1, 8, 20, 40, 42 – 45, 57, 59, and 64 – 66 remain pending. Claims 6 and 7 have been canceled.
Election/Restrictions
2. Applicant's election with traverse of Group I (claims 1, 2, 6 – 10, and 16 – 17) in the reply filed on 11/21/2023 is acknowledged. The traversal is on the ground(s) that the Examiner has not shown that a serious burden would result if all of the claims are examined together. Applicant notes that the restriction requirement does not provide sufficient basis to indicate that examination of more than one of the “groups: would overly burden the Examiner. This is not found persuasive because the claims are directed to distinct inventions (Groups I, II, III, IV, and IV as set forth in the Office Action dated 10/17/2023) with different classifications and each would require a different field of search.
The requirement is still deemed proper and is therefore made FINAL.
3. Claims 20, 40, 42 – 45, 57, 59, and 64 -66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/21/2023.
4. Claims 1 and 8 are under consideration.
Priority
5. This application claims the benefit of the filing date of U.S. Provisional Application
62/741,971, which was filed on October 5, 2018.
Withdrawn Claim Objection
6. The objection to claim 1 is rendered moot by Applicant’s deletion of “DREADD” in the claim.
Withdrawn Claim Rejections - 35 USC § 112
7. The rejection of claim 6 under 35 U.S.C. 112(d) is rendered moot by Applicant’s cancellation of the claim.
Claim Rejections - 35 USC § 103
8. The rejection of claim 1 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to the claim.
9. The rejection of claims 6 and 7 is rendered moot by Applicant’s cancellation of these claims.
10. The rejection of claim 8 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 1.
Rejections Necessitated by Amendments
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.
11. Claims 1 and 8 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 instant claims are drawn to a nucleic acid construct comprising a sequence of a PAR that is not activated by thrombin. Thus, the claims are broadly drawn to any nucleic acid sequence of a PAR that is not activated by thrombin. Therefore, the claims are considered genus claims that encompass a wide array of sequences. The claims encompass any PAR sequence that is not activated by thrombin which is not described by their function, structure or relation thereto. The genus for the PAR sequence that is not activated by thrombin is highly variant, inclusive to numerous structural variants because a significant number of structural differences between genus members is permitted.
The specification does not describe any sequences of a PAR that is not activated by thrombin. However, the specification contemplates a directed molecular evolution approach to facilitate the creation of a family PARS to be activated by clozapine-N-oxide but not by its native ligand thrombin (page 41, lines 9 – 12). The specification does not disclose the diverse genus. The specification does not place any structure, chemical or functional limitations on the embraced by genus PAR4 sequence that is not activated by thrombin and recitation of “not activated by thrombin” does not convey a common structure or function and is not so defined in the specification. In sum, specification and the claim do not provide any guidance on the structure of the PAR sequence “not activated by thrombin”.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claims are broad generics, with respect to all of the potential species of antagonists that may exhibit one, all, of or any of the claimed activity. The possible variations of compounds are limitless with potentially thousands of compounds that may exhibit the claimed activities. The purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed by them. A patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that the inventor invented the claimed invention. Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
The specification lacks sufficient variety of species of sequences to reflect this variance in the genus since the specification does not provide any examples of such a genus of sequences. Accordingly, the specification fails to provide adequate written description for the genus of a sequence of a modified PAR that is “not activated by thrombin” and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed had possession of the entire scope of the claimed invention. Moreover, the specification neither describes the complete structure of a representative number of species, nor describes a representative number of species in terms of partial structure and relevant identifying characteristics. Absent of such teachings and guidance as to the structure and function of this sequence, the specification does not describe the claimed sequence in such full, clear, concise and exact terms so as to indicate that Applicant had possession of these sequences at the time of filing of the present application. Thus, the written description requirement has not been satisfied.
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.
12. Claim(s) 1 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Nissim (US-20100197767-A1; Filed 07/10/2008, Published 08/05/2010; previously cited), hereinafter Nissim in view of Arachiche (Arachiche, Amal, et al. Journal of Biological Chemistry 288.45 (2013): 32553-32562.), hereinafter Arachiche in view of Deans (WO-2017011550-A1; Filed 07/13/2016, Published 01/19/2017; previously cited), hereinafter Deans which is cited on the IDS filed 08/12/2022 in view of Tiedt (Tiedt, Ralph, et al. Blood 109.4 (2007): 1503-1506; previously cited), hereinafter Tiedt.
Regarding claim 1, Nissim teaches a nucleic acid construct system comprising a first nucleic acid operably linked to a first inducible mammalian transcription regulatory sequence that may be a promoter sequence (claim 1a); a second nucleic acid operably linked to a second inducible mammalian transcription regulatory sequence that may be a promoter sequence (claim 1b), and a third nucleic acid operably linked to a promoter where the third nucleic acid comprises a therapeutic polypeptide (claim 1c) where all three may be encoded on a single nucleic acid construct (page 2, 0017 – 0021 and 0033; page 4, 0071 – 0076; 0083; page 9, 0129). Nissim teaches it has been demonstrated that engineered gene circuits can be interfaced with natural ones to obtain cells that respond to biological signals in a predetermined way (page 1, 0008). Nissim teaches in Example 5 retroviral delivery of the constructurs where all three modules are encoded in a single retrovirus (page 14, para. 0212 – 0213). Nissim does not teach “a modified protease-activated receptor (PAR), wherein the modified PAR is not activated by thrombin”, “CXCL4, GPIIb, or PTPRC” of claim 1a or “HoxB4 or GATA1” of claim 1b. However, Nissim teaches treating a disease comprising expressing the nucleic acid construct system which is capable of integrating at least two gene input signals with a simple computation to generate a biological output that intervenes with cell-fate (page 2, 0023 – 0027; page 4, 0071). Nissim teaches there has been significant interest in exploring biological computation using biological molecules as input data and biologically active molecules as outputs in a system for logical control of biological processes (page 1, 0006). Nissim teaches there remains a widely recognized need for, and it would be highly advantageous to have, a molecular computing unit capable of integrating more than one signal (page 2, 0016).
Regarding “a modified protease-activated receptor (PAR), wherein the modified PAR is not activated by thrombin” of claim 1a and “PAR4” of claim 8, Arachiche teaches the nucleic acid of a PAR4 with a mutation resulting in R47Q that is not activated by thrombin (page 32554, left col. para. 4; page 32556, left col. last para.). Arachiche teaches PAR4 is the primary signaling receptor on platelets and PAR4 activation produces a prolonged signal that is required for stable clot formation and PAR1 is an excellent thrombin substrate (page 32553, right col. para. 3 – 4). Arachiche teaches thrombin induces the formation of PAR1-PAR4 heterodimers but cleavage-deficient mutants of PAR1 and PAR4 do not form heterodimers when stimulated by thrombin (page 32555, right col. last para.; page 32556, left col. para. 1; page 32560, left col. para. 2). Arachiche teaches the cleavage-deficient PAR4-R47Q did not interact with PAR1 after stimulation of PAR1 (page 32556, left col. para. 2). Arachiche teaches PAR1 and PAR4 form homodimers that is not affected by thrombin (page 32556, right col. para. 2). Arachiche teaches future studies will need to examine how PARs and other GPCRs interact on platelets to mediate their full range of signaling in vivo (page 32561, right col. para. 1). Arachiche teaches a recent Phase III clinical trial with the PAR1 antagonist vorapaxar did not meet its primary end point underscores the need to fully understand the interactions between platelet receptors and how these interactions influence receptor function (page 32561, right col. para. 2). Arachiche teaches understanding the molecular arrangement of PAR1 and PAR4 will provide insight for the development of antiplatelet therapies (page 32561, right col. para. 2).
Regarding “HoxB4 or GATA1” of claim 1b, Deans teaches one or more genetic circuits comprising one or more genes of interest and one or more promoters in an engineered fed cell such that these cells comprising the genetic circuits differentiate into red blood cells or platelets and comprise a therapeutic agent (page 2, lines 1 – 20; Figure 5 – 8 and 11 – 15). Deans teaches the one or more genes of interest of the genetic circuits can be HoxB4 and/or GATA -1 (claim 1b) (page 21, lines 17 – 20; page 26, lines 28 – 29). Deans teaches genetic circuits for the temporal expression of HoxB4 and GATA-1 in Figure 14. Deans teaches regulating the expression of HoxB4 for enhanced HSC proliferation followed by the activation of GATA-1 to commit these cells to the megakaryocyte (MK) lineage for enhanced platelet production (page 34, lines 10 – 28; page 35, lines 9 – 31; Figure 13 – 14). Deans teaches
Deans does not teach “CXCL4, GPIIb, or PTPRC” of claim 1a. However, Deans teaches the one or more genetic circuits can regulate the expression of any the one or more genes of interest (page 21, lines 26 – 29; page 25, lines 6 – 10). Deans teaches genetic circuits can control the expression of the genes of interest in the genetic circuits in response to the addition of chemical inducers to the media to control the differentiation of HSCs to MKs for the production of platelets (page 12, lines 10 – 19; page 14, lines 10 – 15; page 14, lines 17 – 26; page 15, lines 1 – 9; page 16, lines 16 – 17; page 30, lines 20 – 30). Deans teaches the genetic circuit can comprise a promoter that is a tissue-specific or cell-specific promoter (page 19, lines 9 – 12). Deans teaches genetic circuits comprising Cre recombinase to regulate expression of HoxB4 and GATA1 (Figure 10, 14, 15; page 3, lines 25 – 32; page 4, lines 12 – 21). Deans teaches the ability to make platelets in culture would be a valuable clinical and research tool and in vitro systems should be built to accommodate a high production capacity (page 10, lines 15 – 17). Deans teaches a priority of the National Heart, Lung, and Blood institute is to develop and further enhance tools and techniques for regulating stem cell differentiation and maturation to efficiently produce platelets and red blood cells in a cost-effective manner (page 1, lines 15 – 18). Deans teaches platelets are important for hemostasis and thrombocytopenia is a major clinical problem associated with many conditions including myelodysplastic syndromes and chemotherapy where about 1.5 million platelet transfusions are administered each year to prevent severe bleeding and the source of the platelets are human donors (page 1, lines 18 – 24).
Regarding “CXCL4” and “GPIIb” of claim 1a, Tiedt teaches CXCL4 and GPIIb promoters can be used to direct expression of transgenes to megakaryocytes and precursors (Abstract; page 1503, left col. paragraph 1). Tiedt teaches the CXCL4 (Pf4) promoter for expression of Cre-recombinase in megakaryocytes (page 1503, left col. paragraph 1; Figure 1A – C). Tiedt teaches the Cre-mediated excision in megakaryocytes and platelets (page 1505, left col. paragraph 1; Figure 2). Tiedt teaches given the lineage specificity and efficiency of excision, the Pf4-Cre mice promise to be a very useful tool to study megakaryopoiesis, platelet formation and platelet function (page 1505, right col. paragraph 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Nissim regarding a single construct comprising first and second nucleic acid sequences each operably linked to a promoter and a third nucleic acid encoding a therapeutic polypeptide operably linked to a promoter with the teachings of Arachiche regarding a modifed PAR that is not activated by thrombin with the teachings of Deans regarding genetic circuits that can comprise HoxB4 or GATA1 for the production of platelets with the teachings of Tiedt regarding the CXCL4 promoter that directs expression of transgenes to megakaryocytes and precursors to arrive at the claimed nucleic acid construct comprising a first genetic circuit comprising CXCL4 promoter operatively linked to a sequence of a modified PAR4 that is not activated by thrombin, a second genetic circuit comprising a promoter operatively linked to HoxB4 gene, and a third genetic circuit comprising a promoter operatively linked to PAR1. One would have been motivated to combine the teachings of Nissim, Arachiche, Deans, and Tiedt for a nucleic acid construct to produce platelets in vivo to study platelet receptor interactions as Arachiche teaches future studies will need to examine how PARs and other GPCRs interact on platelets to mediate their full range of signaling in vivo. One would have a reasonable expectation of success in combining the teachings as Arachiche teaches R47Q PAR4 is not activated and Deans teaches genetic circuits comprising Cre recombinase to regulate expression of HoxB4 and GATA1 and Tiedt teaches given the lineage specificity and efficiency of excision, the Pf4-Cre mice promise to be a very useful tool to study megakaryopoiesis, platelet formation and platelet function.
Applicant’s Arguments/Response to Arguments
13. Applicant Argues: On page 7 – 8, Applicant asserts that the cited references fail to teach amended claim 1.
Response to Arguments: The prior rejections over the previously cited art have been withdrawn in view of the amendments to the claims. A new rejection is set forth above where Arachiche teaches a nucleic acid of a mutant PAR4 that is not activated by thrombin (page 32554, left col. para. 4; page 32556, left col. last para.). The combined teachings of Nissim (previously cited), Arachiche, Deans (previously cited), and Tiedt (previously cited) make obvious the limitations of claim 1 with motivation to combine the teachings to study platelet receptor function in vivo. A reasonable expectation of success in combining the teachings comes from the teachings of Nissim regarding retroviral delivery of the nucleic acid construct, Dean regarding inclusion of Cre on the genetic circuits and Tiedt regarding Pf4-Cre mice promise to be a very useful tool to study megakaryopoiesis, platelet formation and platelet function.
Conclusion
No claims allowed.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632