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 .
Status of the Claims
Claims 1-15 are currently pending.
Claims 1-15 have been considered on the merits.
Drawings
The drawings are objected to because Fig. 3 and Fig. 4 which represent variant sequences claimed are wholistically blurred and illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 14-15 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (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 or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
(1) The nature of the invention
The specification describes the invention as a mutant of an adeno-associated virus (AAV) capsid protein and to a recombinant virus vector including a mutant of an AAV1 capsid protein which is useful for the expression of a transgene in target pulmonary vessel cells when intratracheally delivered in an aerosol state.
(2) the breadth of the claims:
Claims 14 and 15, broadly encompass a method of preventing or treating pulmonary arterial hypertension comprising administering a pharmaceutical composition comprising a therapeutically effective amount of the recombinant AAV1 vector of claim 5 to a subject. Additionally, claim 15 further limits claim 14 in that the composition is administered by intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subepidermal, intravitreal, intraarticular, subcapsular, subarachnoidal, intraspinal, epidural, or intrasternal injection.
Thus, the claims taken together with the specification imply that the method is able to prevent, or treat pulmonary arterial hypertension using (i) any or no transgene, (ii) in any subject, and (iii) by nearly any method of administration, so long as the vector contains the mutant AAV1 capsid protein, which is unpredictable.
(3) The state of the prior art
The prior art describes the use of AAV delivery vectors as a promising method of delivery for therapeutic transgenes, however the prior art specifically describes aerosolized delivery of specific therapeutic genes which correct specific disease causing mutations or impairments. The art shows that AAV1 capsid proteins are able to target pulmonary tissues, however does not appear to demonstrate that target tissue delivery employing AAV1 capsid proteins itself is a therapeutically effective treatment without a targeted transgene which may treat or prevent the underlying cause of the pulmonary artery hypertension.
(4) the predictability or unpredictability of the art:
The claims embody a method of preventing or treating pulmonary arterial hypertension (i) using any or no transgene, (ii) in any subject, and (iii) by nearly any method of administration, so long as the vector contains the mutant AAV1 capsid protein, which is unpredictable.
(i) using any or no transgene
The method is found to be unpredictable with regards to the ability of the method to prevent or treat pulmonary arterial hypertension through delivering a vector containing a mutant AAV1 capsid protein including either no transgene or in the alternative any transgene. The instant specification only provides examples which employ a vector including a mutant AAV1 capsid protein to demonstrate specified delivery to the target tissue of pulmonary artery tissue, and does not appear to provide any guidance on specific transgenes which may treat the underlying causes of pulmonary artery hypertension. Hadri et al (Circulation, 2013) describes the therapeutic efficacy of delivery of the transgene SERCA2a using a wild-type AAV1 capsid protein (abstract). Hadri describes “SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Over expression of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β galactosidase or saline” (abstract). Hadri is demonstrating that the AAV1 capsid protein is simply a delivery tool and not a therapeutic treatment unless paired with a transgene which targets the underlying cause of pulmonary artery hypertension. Thus, Hadri supports that without a transgene present the method of treatment would be unpredictable for one of ordinary skill in the art.
(ii) in any subject
The method is found to be unpredictable with regards to the ability of the method to prevent or treat pulmonary arterial hypertension in any subject.
The specification demonstrates that the mutant AAV1 capsid is able to target and reach pulmonary cells in a healthy mouse model, C57BL/6 male mouse, as well as in vitro targeting of human pulmonary arterial smooth muscle cells (HPASMCs). Neither of these models of the specification demonstrate an art recognized model of pulmonary arterial hypertension. These models only demonstrate that the mutant AAV1 capsid protein is able to effectively transduce healthy target cells in vitro and in a healthy mouse model. In contrast, Hadri et al describes the use of the wild type AAV vector to deliver a therapeutic gene of interest to mice with demonstrates pulmonary arterial hypertension (abstract). Thus, Hadri supports that the models of the instant specification are not art recognized models of pulmonary artery hypertension, and the specification merely demonstrates that the mutant AAV1 capsid protein is able to transduce target tissue, which is entirely separate from the treatment or prevention of pulmonary arterial hypertension.
Thus, Hadri and the instant specification supports that without a transgene present and an art recognized model the method would be unpredictable for one of ordinary skill in the art to complete without guidance from the instant specification.
(iii) by nearly any method of administration
The method is generally found to be unpredictable in its ability to treat pulmonary arterial hypertension without the inclusion of a specific transgene known or demonstrated to treat or prevent pulmonary arterial hypertension, however the route of administration provides additional uncertainty. The method is found to be unpredictable with regards to the ability of the method to prevent or treat pulmonary arterial hypertension by any route of administration other than the specification demonstrated intratracheal injection and/or aerosolization. The examples provided that utilize the C57BL/6 mouse model were administered the mutant AAV1 capsid protein through the method of intratracheal injection. Additionally, Hadri teaches the administration of the wild type AAV1 vector containing a therapeutic transgene as an aerosolized solution (abstract). These methods of administration provide a nearly direct administration to the target tissue. However, for clarity of the record the addition of the limitation that the vector is administered through intratracheal injection and/or aerosolization will not remedy the overall unpredictable nature of the invention as outlined in this rejection.
Therefore, this method is found to be unpredictable with regards to the method’s ability to prevent or treat pulmonary arterial hypertension.
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented
The specification details examples 1-5. Example 1 details the selection of pulmonary vessel tropic AAV1 capsid protein variants using an AAV library. Example 2 details confirmation of recombinant AAV1 variant infection in C57BL/6 mouse model. Example 3 details confirmation of pulmonary vascular smooth muscle cell targeting efficiency of recombinant AAV1 variant in in C57BL/6 mouse model. Example 4 details confirmation of mobility of recombinant AAV1 variant. Example 5 details confirmation of pulmonary vascular tropism recombinant AAV1 variants.
(7) the presence or absence of working examples:
With specific regards to working examples, the specification teaches specific examples which demonstrate that the mutant AAV1 capsid protein is capable of target tissue transduction. The specification does not provide any examples of treating or preventing pulmonary arterial hypertension in an art recognized disease model.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention within the broad scope as instantly claimed.
It is the examiner’s position that one skilled in the art could not practice the invention
commensurate in the breadth of the claims without undue experimentation. Therefore, claim 14
and its dependents are rejected under 35 U.S.C. 112, first paragraph, for a lack of enablement.
Claims Free of Prior Art
The following is a statement of reasons for the indication of allowable subject matter: Claims 1-8 and 10-13 contain subject matter that appears to be free of the art of a mutant AAV1 capsid protein containing two substitutions which are: serine at position 430 is substituted with cysteine and isoleucine at position 647 is substituted with valine. Additionally, SEQ ID NO 3, the amino acid sequence representing this mutant AAV1 capsid protein and SEQ ID NO 4, the nucleic acid sequence encoding this mutant AAV1 capsid protein are free of the art. The closest art is an art provided by Applicant in the IDS dated 03/20/2026 by inventor Kim et al entitled “A highly mobile adneo-associated virus targeting vascular smooth muscle cells for the treatment of pulmonary arterial hypertension”, dated 04/29/2025, which is not available as prior art. Additionally, it does not appear that it would have been obvious to a person of ordinary skill in the art to specifically choose the substitutions claimed by Applicant based on the teachings of Santiago-Ortiz et al in “AVV ancestral reconstruction library enables selection of broadly infections viral variants” (Gene Therapy, 2015). Santiago-Ortiz teaches about 32 possible amino acid substitution sites in AAV1 capsid proteins which can mediate 19-31 fold higher gene expression in muscle compared to wild type AAV1 and of the 32 sites taught positions 430 and 647 are not described or considered. Thus, it appears that the subject matter of claim 1-8 and 10-11 can be considered free of prior art.
Conclusion
Claims 1-8 and 10-13 are considered free of the prior art. Claims 14-15 are rejected.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
Prosecution Insights