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 .
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 1-7, and the species of shRNA, claims 1-3 and 5, in the reply filed on June 3, 2026 is acknowledged. In view of the allowability of the elected species of shRNA, the species election as set forth in the office action dated April 16, 2026 has been withdrawn and all species of claims 1-7 have been rejoined.
Claims 8-10 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention as not all the claims directed to the elected invention are in condition for allowance (See MPEP 821.04).
Priority
Applicant’s claim for foreign priority to Chinese patent application CN202310137487.7 filed on February 17, 2023. Receipt is acknowledged of certified copies of papers received in the original language as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 30, 2024 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
Objection to the Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description:
Figure 3: Para. [0056]) of the instant specification recites descriptions of the Figure 3 bar graphs labeled A-D however, there are no labels for A, B, C, and D in Figure 3.
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. 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 Objections
Claims 4-7 are objected to because of the following informalities:
Claim 1 recites shRNA which is an abbreviation for “short hairpin RNA”. The full term should be recited followed by the abbreviation in paratheses for the first use of a term.
Claim 4 recites the recombinant expression vector is an expression vector “connecting” shRNA. Connecting an shRNA in an expression vector is not a term of the art. For the purposes of examination the term “connecting” in claim 4 is interpreted to mean “comprising”. Appropriate correction is required.
Claim 5 recites “further comprising: medicinal excipient” in line 2 which appears to be missing the article before “medicinal excipient”. It is recommended that Applicant amend claim 5 to recite “further comprising a medicinal excipient”.
Claim 6 recites abbreviations for the Markush group of promoters. As stated supra, the full term should be used upon first recitation followed by abbreviations in parentheses.
Claim 6 recites “…characterized in that promoter of the expression vector” which appears to be missing the article before “promoter”. It is recommended that Applicant amend claim 6 to recite “…characterized in that a promoter…”
Claim 6 recites “cardiomyocyte specific promoter” in the singular form followed by multiple options of cardiomyocyte specific promoters. It is recommended that Applicant amend claim 6 to recite “cardiomyocyte specific promoters” using the plural forms of promoter.
Claim 7 recites “the host is selected from: virus and/or cell…” which appears to missing the article before “virus and/or cell”. It is recommended that Applicant amend claim 7 to recite “the host is selected from a virus and/or cell”.
Claim 7 recites “the virus is selected from adeno-associated virus” and “the cell is selected from 293 cell”. As claim 7 only recites a single option for the virus and cell it is recommended that Applicant amend to recite that “the virus is an adeno-associated virus” and “the cell is a 293 cell.”
Claim Rejections - 35 USC § 112(a) - Written Description
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 3-7 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 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 inventor or a joint inventor, or for pre-AIA the inventors, at the time the application was filed, had possession of the claimed invention.
Dependent claim 3 encompasses an anti-heart failure drug that is a transformant.
Dependent claims 4-6 encompass an anti-heart failure drug that is a transformant that is host.
Dependent claim 7 encompasses an anti-heart failure drug that is a transformant that is a cell, wherein the cell is a 293 cell.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
ACTUAL REDUCTION TO PRACTICE
In regard to claim 3 encompassing an anti-heart failure drug that is a transformant, the specification indicates that the claimed transformant is a host cell (Para. [0038]) which is transformed with a recombinant expression vector which expresses an shRNA having SEQ ID NOs 1, 3, or 5 (Para. [0080]). Based on Applicant’s disclosure, 293T cells were utilized in order to generate a recombinant AAV9 (rAAV9) which expressed the shRNA (See Section 6 at Para. [00128] and Section 7 at Para. [00131]) and the rAAV9 expressed an shRNA having SEQ ID NO: 1 was used as an anti-heart failure drug (See Example 2).
In regard to dependent claims 4-6 encompassing an anti-heart failure drug that is a transformant that is host, the specification indicates that the claimed transformant is a host cell (Para. [0038]) which is transformed with a recombinant expression vector which expresses an shRNA having SEQ ID NOs 1, 3, or 5 (Para. [0080]). Based on Applicant’s disclosure, 293T cells were utilized in order to generate a recombinant AAV9 (rAAV9) which expressed the shRNA (See Section 6 at Para. [00128] and Section 7 at Para. [00131]) and the rAAV9 expressed an shRNA having SEQ ID NO: 1 was used as an anti-heart failure drug (See Example 2).
In regard to dependent claim 7 encompassing an anti-heart failure drug that is a transformant that is a cell, wherein the cell is a 293 cell, the specification indicates that the claimed transformant is a host cell, preferably a 293 cell (Para. [0038]) which is transformed with a recombinant expression vector which expresses an shRNA having SEQ ID NOs 1, 3, or 5 (Para. [0080]). Based on Applicant’s disclosure, 293T cells were utilized in order to generate a recombinant AAV9 (rAAV9) which expressed the shRNA (See Section 6 at Para. [00128] and Section 7 at Para. [00131]) and the rAAV9 expressed an shRNA having SEQ ID NO: 1 was used as an anti-heart failure drug (See Example 2).
Accordingly, Applicant did not demonstrate a reduction to practice a genus of claimed transformants which are host cells and/or 293 host cells which are able to serve as anti-heart failure drugs. Furthermore, Applicant has not adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of hosts which would predictably function as anti-heart failure drugs.
DISCLOSURE OF STRUCTURE
The Applicant has provided a limited number of species of the claimed transformants (i.e., a 293 cell) which were used in order to generate an rAAV9 which expresses an anti-heart failure drug which is an shRNA. Although Applicant reduced to practice function of the rAAV9 which expresses SEQ ID NO: 1 as an anti-heart failure drug (Example 2), Applicant provides no structure or guidance regarding administration of a transformant which is a 293T cell as an anti-heart failure drug.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making and using the claimed invention is not well established. Although not disclosed in the instant specification, it appears that the shRNAs target a portions of ankyrin repeat domain 1 (Ankrd1), also called cardiac ankyrin repeat protein (CARP), mRNA in mouse (SEQ ID NO: 1) and human (SEQ ID NO: 3 and 5). Applicant’s instant specification indicates that administration of SEQ ID NOs 1, 3, and 5 resulted in reduced mRNA expression of atrial natriuretic peptide (ANP) in cardiomyocytes (Figure 1) and systemic administration of an AAV9 vector expressing SEQ ID NO: 1 prior to transverse aortic constriction surgery resulted in improved indicators of cardiac function compared to administration of a control AAV (Para. [00148], Figure 3).
Use of rAAVs for delivery of various polynucleotides, including shRNA is well known in the art. The role of ANKRD1 in cardiac injuries and heart failure and use of an rAAV expressing an shRNA targeting Ankrd1/Carp for treatment of cardiac dysfunction was also known in the art at the time of filing. The prior art of Chen et al. (2014, Cytosolic CARP promotes angiotensin II-or pressure overload-induced cardiomyocyte hypertrophy through calcineurin accumulation. PLoS One, 9(8), e104040) discloses that upregulation of Ankrd1 enhances hypertrophy and upregulates atrial natriuretic peptide in cardiomyocytes as well as increases CARP and heart/body weight ratio in mice with transverse aortic constriction (TAC). Chen et al. also discloses that shRNA targeting Ankrd1 inhibited (TAC) induced hypertrophy. Chen et al. discloses that intraventricular administration of an rAAV2/9 encoding an shRNA targeting Ankrd1 to mice prior to TAC (Pg. 5, left col., 1st para.) inhibits cardiac hypertrophy (Pg. 7, left col., 2nd full para.).
However, the art is silent as to administration of 239T cells in gene therapy. Although use of 293T cells are well known for the production of viral vectors, administration of 293T cells is thought to be unsafe. Debeb et al. ( 2010, Characterizing cancer cells with cancer stem cell-like features in 293T human embryonic kidney cells. Molec. Cancer, 9(1), 180) discloses that 293T cells have a cancer stem cell like phenotype and form aggressive tumors when transplanted (Abstract). Therefore, a skilled artisan would not be likely to utilize 293T cells for administration as an anti-heart failure drug.
Applicant has claimed a genus of transformants which are able to function as an anti-heart failure drug, yet the specification has not disclosed such genus, and has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of transformants which are capable of functioning as an anti-heart failure drug. Furthermore, the state of the art indicated that making the claimed genus of transformants that can predictably function as an anti-heart failure drug is not well established and would require undue experimentation. Therefore, although administration of an rAAV encoding an shRNA targeting Ankrd1 was known to function as an anti-heart failure drug, one of skill in the art would neither expect nor predict administration of a transformant which is a host 293 cell comprising the rAAV to result in the claimed functional effect of serving as an anti-heart failure drug.
CONCLUSION
Therefore, the Examiner concludes that there is insufficient written description of the instantly claimed genus of transformants which are host cells and/or 293 cells. Specifically, there is limited description of the structure-function relationship between the claimed genus of transformants and their ability to predictably function as anti-heart failure drug.
Claim Rejections - 35 USC § 112(b)
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 1-7 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 6 is included in the rejection as incorporating the limitations of a rejected claim from which it depends while failing to correct the deficiencies.
Claims 1 and 2, as instantly claimed, appear to recite that the shRNA is a DNA sequence rather than an RNA sequence thus rendering the claims indefinite. It is recommended that Applicant amend claims 1 and 2 for clarity. Based on Applicant’s specification, it is recommended that Applicant amend claims 1-2 to recite “An shRNA that is expressed by a DNA sequence selected from…”
Claims 3 and 4 recites the limitation "the shRNA has a sequence shown as SEQ ID NO: 1" and “the shRNA with sequence shown at SEQ ID NO: 1” in lines 4 and 3, respectively. There is insufficient antecedent basis for these limitations in the claims as the previous recitations of the shRNA indicate that SEQ ID NOs: 1, 3, and 5 are DNA sequences, not RNA sequences. Appropriate correction is required. It is recommended that Applicant amend to maintain consistent language indicating the instantly claimed SEQ ID NOs are DNA sequences.
Claim 5 which depends from claims 3 and 3, recites “The anti-heart failure drug according to claim 3 characterized in that…an anti-heart failure drug…”. Use of “an anti-heart failure drug” following recitations of “the anti-heart failure drug” renders the scope of the claim unclear. Specifically, it is unclear whether this is intended to refer to the anti-heart failure drug as recited in claim 2 from which claim 5 depends or a different anti-heart failure drug. Appropriate correction is required. It is recommended that Applicant amend such that the claim reads “…characterized in that the anti-heart failure drug…”.
Claim 7 recites a host which is selected from a “virus and/or a cell, and/or the virus is selected from adeno-associated virus and/or the cell is selected from 293 cell”. The repeated use of and/or renders the scope of the claim unclear as it is difficult to determine which hosts or combinations of hosts encompassed by the claim. Appropriate correction is required. It is recommended that Applicant amend to recite “the host is selected from a virus and/or cell; wherein, the virus is an adeno-associated virus; wherein, the cell is a 293 cell”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3-7 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3, which depends from claim 2, recites the “anti-heart failure drug according to claim 2 characterized in that the active pharmaceutical ingredient is selected from…shRNA, a recombinant expression vector, and a transformant…”. However, the anti-heart failure drug of claim 2 recites that the active pharmaceutical ingredient comprises shRNA with no recitation of a recombinant expression vector or transformant. It is unclear how the recombinant expression vector, and a transformant further limit the shRNA of claim 2. The Examiner recommends Applicant amend the claim to include that the recombinant expression vector comprises the shRNA of claim 2, and the transformant comprises the shRNA of claim2
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Allowable Subject Matter
Claims 1 and 2 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, 2nd paragraph, set forth in this Office action.
Applicant’s invention of claims 1 and 2 recite a shRNA characterized as having a DNA sequence selected from SEQ ID NO: 1, SEQ ID NO: 3, and SEQ ID NO: 5 and an anti-heart failure drug comprising an active pharmaceutical ingredient which comprises shRNA characterized as having a DNA sequence selected from SEQ ID NO: 1, SEQ ID NO: 3, and SEQ ID NO: 5.
Although not disclosed in the instant specification, it appears that the shRNAs target a portions of ankyrin repeat domain 1 (Ankrd1), also called cardiac ankyrin repeat protein (CARP), mRNA in mouse (SEQ ID NO: 1) and human (SEQ ID NO: 3 and 5). Applicant’s instant specification indicates that administration of SEQ ID NOs 1, 3, and 5 resulted in reduced mRNA expression of atrial natriuretic peptide (ANP) in cardiomyocytes (Figure 1) and systemic administration of an AAV9 vector expressing SEQ ID NO: 1 prior to transverse aortic constriction surgery resulted in improved indicators of cardiac function compared to administration of a control AAV (Para. [00148], Figure 3).
Zhang et al. (2021, Cardiac ankyrin repeat protein contributes to dilated cardiomyopathy and heart failure. The FASEB Journal, 35(4), e21488) discloses that overexpression of CARP/ANKRD1 in mice results in dilated cardiac chambers, impaired heart function, cardiac fibrosis, and reduced survival in response to cardiac injury (Abstract). Zhang et al. discloses that mutations of CARP/ANKRD1 have been identified in human patients having hypertrophic cardiomyopathy and idiopathic dilated cardiomyopathy and that CARP has been found to be upregulated in patients with end stage heart failure (Pg. 2, left col., 1st full para.). Zhang et al. further discloses that CARP is known as a stress-response protein which can be activated by cardiac injuries and that CARP has been shown to be upregulated in heart failure in various cardiomyopathies (Pg. 9, left col., last para.) and suggests that CARP could be a causative factor for dilated cardiomyopathy and is therefore a promising therapeutic target (Pg. 9, right col., top para.).
Chen et al. (2014, Cytosolic CARP promotes angiotensin II-or pressure overload-induced cardiomyocyte hypertrophy through calcineurin accumulation. PLoS One, 9(8), e104040) discloses that upregulation of Ankrd1 enhances hypertrophy and upregulates atrial natriuretic peptide in cardiomyocytes as well as increases CARP and heart/body weight ratio in mice with transverse aortic constriction (TAC). Chen et al. also discloses that shRNA targeting Ankrd1 inhibited (TAC) induced hypertrophy. Chen et al. discloses that intraventricular administration of an AAV encoding shRNA targeting Ankrd1 to mice prior to TAC (Pg. 5, left col., 1st para.) inhibits cardiac hypertrophy (Pg. 7, left col., 2nd full para.). Chen et al. is silent as to the specific sequence of shRNA but appears to suggest that a rat Ankrd1 sequence was used for the overexpression AAV (Pg. 2, right col., last para.). Chen et al. concludes that pharmacological inhibition of Ankrd1/CARP could be used as a treatment for cardiac hypertrophy (Pg. 11, right col., last para.).
Yuan et al. (2025, ANKRD1 knockdown attenuates doxorubicin-induced dilated cardiomyopathy by regulating mitochondrial dysfunction and oxidative stress through activation of the AMPK/AKT/mTOR pathway. Electronic J. of Biotech.) discloses that elevated AKNRD1 levels are known to be correlated with cardiac disease progression and ANKRD1 expression can be used as a biomarker for dilated cardiomyopathy versus non-heart failure states (Pg. 2, right col., 1st full para.). Yuan et al. discloses use of an vector expression shRNA targeting ANKRD1 in order to knockdown ANKRD1 in rats (Pg. 3, left col. 2nd para.) but is silent as to the specific sequence of shRNA. Yuan et al. discloses that shRNA mediated knockdown of ANKRD1 attenuates cardiac dysfunction associated with induced dilated cardiomyopathy (Fig. 3, and Pg 8, right col., last para.). Yuan et al. concludes that ANKRD1 is a potential target for clinical interventions including AAV9-based gene therapies and small molecule inhibitors (Pg. 10, right col., last para.).
Thus, although the role of ANKRD1 in cardiac injuries and heart failure is known in the art and shRNA targeting Ankrd1/Carp for treatment of cardiac dysfunction is known in the art the existing prior art does not appear to fairly teach or suggest and shRNA having a DNA sequence of the instantly claimed SEQ ID NOs: 1, 3, and 5.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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