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 .
Application Status, Priority and Withdrawn Rejections
Applicant’s amendments filed August 13, 2026, amending claims 1, 6-7, 11 and 13, canceling claims 2, and 4-5, and adding new claim 14 is acknowledged. Claims 1, 3 and 6-14 are pending and under examination.
The amended claims limiting the nuclease to a Cas9 nuclease and removing “multifunctional” are fully supported in the Provisional Application Nos. 62/899,584 and 62/757,679. However, the earliest provisional application, 62/757,679, does not recite methods for treating septicemia. Therefore, the effective filing date of the claimed method is September 12, 2019.
The cancelation of claim 5 renders the §112(d) rejection moot.
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, 3, and 6-14 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a new rejection, necessitated by amendment. It is modified to address the added limitations in claim 1 and the change preamble language.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of Claims
The claims are drawn to a method of reducing symptoms associated with septicemia in a subject. The Specification does not define “treatment of” or “reducing symptoms associated with” septicemia. Without a limiting definition, “reducing symptoms associated with septicemia” is not patentably distinct from “treating septicemia”. The method comprises the step of "administering to the subject with septicemia a therapeutically effective amount of a pharmaceutical composition” that comprises a viral vector comprising “a nucleotide sequence encoding a guide RNA (gRNA) comprising (i) a nucleic acid encoding a guide sequence with SEQ ID NO 1-4 (i.e., comprising only 14 nucleotides) that is complementary to a portion of the MyD88 promoter and (ii) an MS2 aptamer target site specific for an RNA binding bacteriophage MS2 coat protein" and "a Cas9 nuclease". Based on the description in the Specification the synthetic repression system inhibits transcription based on using short guide RNAs and a repression domain recruited to the MyD88 promoter by the Cas9/sgRNA complex. Thus, the nature of the invention is complex in that the claims require the administration of the composition to the genus of all subjects with existing septicemia, including both mice and humans. Furthermore, claim 12 further requires "administering to the subject additional doses of the synthetic repression system composition until the level of the at least one immune related marker is reduced." The nature of the invention is complex in that the administration must be sufficient to reduce symptoms associated with septicemia and reduce the level of at least one immune related marker with single or multiple administrations of the composition. Finally, the method requires a guide RNA with guide sequence comprising SEQ ID NOs 1-4, which the Specification provides targets the mouse MyD88 promoter.
Accordingly, enablement of the method requires one skilled in the art to be able to predictably reduce symptoms associated with septicemia (i.e., to treat septicemia) in the genus of all subjects and reduce the level of at least one immune-related marker with single or multiple administrations of a viral vector-based delivery system encoding Cas9 nuclease and guide RNAs targeted to the promoter of the mouse MyD88 gene.
Guidance in the Specification and existence of working examples
The specification envisions using the disclosed compositions for treating septicemia (e.g., [0009], [0030] and [0060]). The specification provides general guidance with regard to the formulation of pharmaceutical compositions (e.g., [0060]). The working example makes use of Cas9 nuclease transgenic mice (e.g., [0091]). The reasoning provided by the inventor in the disclosure is that "they enable us to eliminate potential confounding effects associated with delivery of Cas9." See [0091]. The specification discloses the pre-treatment of Cas9 mice with AAV/Myd88-MS2-HPlaKRAB or AAV/Mock, and three weeks later subjecting the mice to systemic lipopolysaccharides (LPS) from Escherichia coli 0127:B8 (e.g., [0098]-[0099]). The pre-treatment with AAV/Myd88-MS2-HP1aKRAB resulted in a reduction in Myd88 expression, a reduction in expression of downstream markers, such as Icam-1, Tnfa, Ncf, Il6, Ifn-a, Ifn-b, Ifn-g, and Stat4, and a reduction in serum lactate level as compared to the mock-treated mice (e.g., [0098]; Figs. 2C, 2D, 2F. 6 and 7).
There is no working example of the claimed invention. There is no evidence that the administration of the claimed composition can reduce the symptoms of septicemia already present in a subject. There is no evidence that repeated administration of the composition provides for effective treatment when a single administration may not. There is no evidence of the claimed guide RNA targeting sequences in the MyD88 gene in any subject besides mice.
Accordingly, in light of the specification, it is highly unpredictable if the system comprising Cas9 and a mouse-MyD88-promoter-targted gRNA delivered via a viral vector to a subject already having septicemia would actually reduce symptoms in mice specifically, or in the genus of individual subjects.
Predictability and State of the Prior Art
The prior art teaches that the administration of pioglitazone antagonizes PPAR-y and results in a decrease in MyD88 expression in vivo (Ferreira et al., The Journal of Immunology, (2014), 192: 2357-2365, Figure S1, Abstract; Fig. 6C; of record). Ferreira teaches the administration of pioglitazone 1, 4 and 18 hours before CLP surgery to induce sepsis in mice (e.g., page 2358, left column). Ferreira teaches “Treatment of mice with pioglitazone (20 mg/kg) for 1 or 4 h before CLP did not have any effect on survival in animals with moderate or severe sepsis (Supplemental Fig. 1). When mice were treated with pioglitazone for 18 h before CLP, we observed a significant increase in the survival of severely septic mice but no effect on the survival of moderately septic mice (Fig. 1A)” (¶ spanning pates 2358-2359). Ferreira teaches that prolonged activation of PPAR-y (pharmacological treatment 18 hours prior to CLP) protects mice against severe polymicrobial sepsis by mechanisms that include inhibition of MyD88 expression (e.g., ¶ bridging pages 2358-3559; page 2362, ¶ bridging columns; Fig. 1A). Given that the prior art teaches that only prolonged pretreatment is able to reduce symptoms of septicemia, one would have understood that treatment of a subject already experiencing septicemia would have been unpredictable. This is consistent with the example in the disclosure, which uses pre-treatment of mice prior to LPS exposure to demonstrate an effect. In contrast, the claims require the subject to have septicemia prior to treatment.
Park provides a prophetic example of using nanovesicles comprising MyD88-targeted siRNAs to treat sepsis (US 20200163998 A1, [0207]; of record). However, as the example is merely prophetic, it does not provide any predictability for the effectiveness of inhibiting MyD88 as a treatment for patients with existing sepsis.
Hattori reviews the state of the art of using gene therapy-based approaches for sepsis as of 2018, approximately 18 months before the effective filing date of the claimed invention (Hattori et al., European Journal of Pharmacology (2018), 833: 403-410; of record). Hattori teaches that ODN decoys that block transcription factor protein function could be a viable therapeutic (e.g., Section 2). Given that MyD88 is not a transcription factor and does not bind DNA, using nucleic acids to block MyD88 activity is not a viable option. Hattori concludes “there is likely to be modulation rather than inhibition of NF-κB activation that is more effective in preventing multiple organ injury and improving survival in sepsis” (Section 2, last sentence). This underscores the uncertainty of being able to alter the expression of a single gene as an effective treatment for sepsis. Hattori suggests using siRNAs or miRNAs as a treatment for sepsis (Sections 4-5), but concludes by stating “While gene therapy is an attractive therapeutic option and holds enormous promise for potentially providing a curative therapy to septic patients, significant technical challenges have to be addressed to deliver and transfer the genetic therapy substances into the body in a safer and more effective way prior to the clinical application of gene therapy for sepsis.” (Section 6, last sentence). Thus, it was completely unpredictable around the effective filing date of the claimed invention if nucleic acid-based therapies, including delivery by viral vectors, would be an effective at reducing symptoms for a patient with sepsis.
Thus, in view of the prior art, it is highly unpredictable if the system comprising Cas9 and a mouse-MyD88-targted gRNA delivered via a viral vector to a subject already having septicemia would actually treat the individual.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, and the lack of working examples of actually reducing symptoms of septicemia in a subject already having sepsis, it is the conclusion that an undue experimentation would be required to make and use the invention.
Response to Arguments
Applicant argues that the claims as amended are fully enabled (Remarks, page 6, ¶1). This argument has been fully considered but is not persuasive as it is merely arguments of counsel. MPEP 716.01(c) makes clear that arguments of counsel cannot take the place of evidence in the record. Applicant does not provide any evidence that the synthetic repression system could treat and/or prevent symptoms in a subject already having septicemia (i.e., other than pre-treatment), which is the central issue noted in the enablement rejection above.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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