DETAILED ACTION
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 Response to Election/Restriction Filed, Amendment, and Arguments/Remarks, filed 09 September 2025, have been entered. Claims 1-13 are currently pending in the application. Claims 1, 6, 12, and 13 are independent claims. Applicant’s election of the following species:
Insertion positions: a. Amino acid No. 587,
Inserted amino acid sequences: a. SEQ ID NO: 1
with traverse in a reply filed 09 September 2025 is acknowledged.
Applicant argues that no supporting evidence was provided by the Office Action as to why or how the USPTO has reached the conclusion that the species are deemed to lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1.
However, this is not agreed.
The Requirement for Restriction/Election mailed 12 June 2025 includes an explanation of the rationale for the conclusion that the species are deemed to lack unity of invention on page 4 lines 18-23. Therefore, Applicant’s arguments are not found persuasive in traversing the election of species requirement. As such, the election of species requirement is still deemed proper and is therefore made FINAL.
Claims 1-13 are currently pending in the application and under examination to which the following grounds of rejection are applicable. An action on the merits follows.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2021/054347, filed 22 February 2021, which claims priority to EPO 20158633, filed 20 February 2020. Filing of a certified copy of the EPO 20158633, filed 20 February 2020is acknowledged.
Thus, the earliest possible priority for the instant application is 20 February 2020.
Information Disclosure Statement
The information disclosure statements filed 17 August 2022 have been considered by the Examiner.
Specification
The disclosure is objected to because of the following informalities: the Brief Description of the Drawings does not include a description of each panel. Specifically, the descriptions of Figures 3A-C, 4A-B, 5A-D, 6A-B, 7B-E, and 7H-I do not include individual descriptions of each panel. See MPEP 608.01(f), which states, “When there are drawings, there shall be a brief description of the several views of the drawings and the detailed description of the invention shall refer to the different views by specifying the numbers of the figures, and to the different parts by use of reference letters or numerals”. Further, MPEP 608.01(f) instructs Examiners such that “If the drawings show Figures 1A, 1B, and 1C and the brief description of the refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1B, and 1C.” Appropriate correction is required.
The use of the terms “MACS” on page 12, “DNEasy Blood and Tissue kit” on page 13, “TaqMan” on page 15, “TaqMan Fast Advance Master Mix” on page 15, “TaqMan Copy Number Assay” on page 15, “RNasin” on page 16, and “SYBR” on page 16, , which are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms. Note that the specification has not been inspected sufficiently to identify all instances of trade names and/or marks used. It is Applicant’s responsibility to ensure full compliance.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 1-13 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.
Independent claim 1 has multiple issues of indefiniteness.
Claim 1 recites, “a nucleic acid construct for an effector molecule”, which is indefinite because it is unclear in what way a nucleic acid construct is “for” an effector molecule. For example, it is unclear whether the nucleic acid construct comprises or encodes the effector molecule, or whether the nucleic acid construct somehow supports an effector molecule functionally, structurally, or in some other way.
Claim 1 recites an “AAV2 viral vector particle comprising a nucleic acid construct for an effector molecule, comprising a capsid protein (CAP)”, which is indefinite because it is unclear whether the effector molecule is meant to comprise the CAP protein or whether the AAV2 viral vector particle itself (and not the effector molecule) is meant to comprise the CAP protein.
In the interest of compact prosecution, claim 1 has be interpreted such that the AAV2 viral vector particle comprises both a nucleic acid construct for an effector molecule and a capsid protein.
Claim 1 also recites, “comprising SEQ ID NO: 1”, which is indefinite because it is unclear how a capsid protein can comprise a sequence identifier itself rather than the sequence of the sequence identifier.
As such, the metes and bounds of the claim cannot be determined.
Claim 5 recites the AAV2 viral vector particle according to claim 1, comprising mutations R585A and R588A, which is indefinite because claim 1 recites that CAP protein is the wild-type CAP protein sequence of SEQ ID NO: 56 comprising an inserted amino acid section (e.g., SEQ ID NO: 1) C-terminal to amino acid No. 587 (as elected). As such, it is unclear how the wild-type sequence of SEQ ID NO: 56 also comprises the mutations recited in claim 5, and the limitations of claim 5 therefore conflicts with the limitations of claim 1. As such, the metes and bounds of the claim cannot be determined.
Claim 6 recites, a composition comprising the AAV2 viral vector particle according to claim 1 and adapted for administering”, which is indefinite because it is unclear in what way the AAV2 particle of claim 1 is “adapted” for the administering. For example, it is unclear whether “adapted” requires structural limitations or is merely reciting an intended use for the composition. As such, the metes and bounds of the claim cannot be determined.
Claim 7 recites the composition of claim 6 wherein the AAV2 viral vector particle contains a nucleic acid construct comprising an effector sequence, which claim 8 recites is an expression cassette encoding an effector molecule. As such, it is unclear whether the nucleic acid construct of claims 7 and 8 is the same nucleic acid construct recited in claim 1 (upon which claim 6 depends) or whether it represents an additional nucleic acid construct. As such, the metes and bounds of the claim cannot be determined.
Claim 9 recites the limitation "the disease" in line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 9 is dependent on claim 6, which recites “a disease or defect of cardiac myocytes” and “a disease or defect of muscular myocytes or of skeletal muscle cells”. As such, the metes and bounds of the claim cannot be determined.
Claim 10 recites the limitation "the treatment" in line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 9 is dependent on claim 6, which recites “treatment of a disease or defect of cardiac myocytes” and “treatment of a disease or defect of muscular myocytes or of skeletal muscle cells”. As such, the metes and bounds of the claim cannot be determined.
Independent claim 12 has multiple issues of indefiniteness.
Claim 12 recites a process for producing AAV2 viral vector particles by delivery of components for AAV vector production, cell lysis, removal of cellular components and plasmid DNA, and further purification of AA viral vector particles. The term “for” renders the claim indefinite because it is unclear whether the subsequent actions of delivery, lysis, removal, and purification are part of the preamble of the claim or whether they represent active method steps. If active method steps, it is further indefinite whether they are a closed set of steps of the method or whether the method comprises the listed steps.
Claim 12 also recites wherein the AAV2 viral vector particle comprises a CAP which C-terminally to amino acid No. 587 (as elected) of the wild-type amino acid sequence of CAP contains an inserted amino acid section. However, claim 12 does not provide a reference sequence to determine which amino acid is amino acid number 587 of the wild-type sequence of CAP.
In the interest of compact prosecution, claim 12 has been interpreted as though the process comprises the listed steps as active steps of the process and such that the wild-type amino acid sequence of CAP is that set forth in instant SEQ ID NO: 56.
As such, the metes and bounds of the claim cannot be determined.
Claims 2-3, 11, and 13 hare included in this rejection due to their dependence on or encompassing of independent claim 1.
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 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
An AAV2 viral vector particle comprising:
a nucleic acid construct comprising an expression cassette encoding an effector molecule, and
a capsid protein (CAP) which comprises an insert amino acid sequence C-terminal to amino acid No. 587 of the CAP wild-type amino acid sequence according to SEQ ID NO: 56, wherein the insert amino acid sequence comprises:
an N-linker AAA or ASA amino acid sequence immediately C-terminal to amino acid No. 587,
the sequence of SEQ ID NO: 1 immediately C-terminal to the N-linker sequence, and
a C-linker AA amino acid sequence immediately C-terminal to the sequence of SEQ ID NO: 1,
wherein the effector molecule is long noncoding RNA (lncRNA) H19, and
wherein the AAV2 viral vector particle is for administering to treat a disease or defect of cardiac myocytes, and
wherein the disease or defect of cardiac myocytes is pathological cardiac hypertrophy;
A process for producing AAV2 viral vector particles, comprising:
delivery of components for AAV vector production in a cultivated eukaryotic HEK293 cell, followed by
cell lysis and removal of cellular components and plasmid DNA, and
further purification of AAV viral vector particles,
wherein the AAV2 viral vector particle comprises:
a nucleic acid construct comprising an expression cassette encoding an effector molecule, and
a modified capsid protein (CAP) which comprises an insert amino acid sequence C-terminal to amino acid No. 587 of the CAP wild-type amino acid sequence according to SEQ ID NO: 56, wherein the insert amino acid sequence comprises:
an N-linker AAA or ASA amino acid sequence immediately C-terminal to amino acid No. 587,
the sequence of SEQ ID NO: 1 immediately C-terminal to the N-linker sequence, and
a C-linker AA amino acid sequence immediately C-terminal to the sequence of SEQ ID NO: 1,
wherein the effector molecule is long noncoding RNA (lncRNA) H19, and
wherein the AAV2 viral vector particle is adapted for administering to treat a disease or defect of cardiac myocytes,
wherein the disease or defect of cardiac myocytes is pathological cardiac hypertrophy,
wherein the components for AAV vector production comprise:
an AAV helper plasmid comprising a nucleic acid sequence encoding
the modified CAP protein, and
a wild-type AAV2 Rep proteins,
an adenoviral helper plasmid, and
an AAV vector genome plasmid comprising the nucleic acid construct;
and
A method of treatment for a cardiac disease or a cardiac defect, comprising administering the AAV2 vector particle according to claim 1 (as described in (1) above) to a patient who is diagnosed as having the cardiac disease or cardiac defect,
wherein the nucleic acid construct comprises an expression cassette encoding an effector molecule,
wherein the cardiac disease or cardiac defect is pathological cardiac hypertrophy, and
wherein the effector molecule is long noncoding RNA (lncRNA) H19;
does not reasonably provide enablement for:
An AAV2 viral vector particle comprising any nucleic acid construct for any effector molecule, comprising any capsid protein (CAP) which C-terminally to amino acid NO. 587 of the wild-type amino acid sequence of CAP of SEQ ID NO: 56 contains an inserted amino acid section comprising SEQ ID NO: 1, wherein the inserted amino acid section does not comprise an N-linker AAA or ASA amino acid sequence and a C-linker AA amino acid sequence flanking the sequence of SEQ ID NO: 1, and wherein the AAV2 viral vector particle is for any use;
A process for producing AAV2 viral vector particles by delivery of any components for AAV vector production in any cultivated eukaryotic cell, followed by cell lysis and removal of cellular components and plasmid DNA, and further purification of AAV viral vector particles, wherein the AAV2 viral vector particles comprises any CAP which C-terminally to amino acid NO. 587 of the wild-type amino acid sequence of CAP contains an inserted amino acid section comprising SEQ ID NO: 1, wherein the inserted amino acid section does not comprise a 3x alanine N-linker and a 2x alanine C-linker flanking the sequence of SEQ ID NO: 1, and wherein the AAV2 viral vector particle is for any use; nor
A method of treatment for any cardiac disease, including cardiac defects, comprising administering the AAV2 vector particle according to claim 1 to any patient who is diagnosed as having the cardiac disease or cardiac defect, wherein the nucleic acid construct comprises any sequence encoding any effector molecule.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
This rejection comprises four (4) separate issues:
1) the absence of an enabling disclosure for an AAV2 viral vector particle comprising a modified CAP protein comprising an inserted amino acid section comprising the sequence of SEQ ID NO: 1 without additional N-linker AAA or ASA amino acid sequence and C-linker AA amino acid sequence flanking the sequence of SEQ ID NO: 1;
2) the absence of an enabling disclosure for a process for producing AAV2 viral vector particles by delivery any components for AAV vector production other than components comprising a) an AAV helper plasmid comprising a nucleic acid sequence encoding i) the modified CAP protein, and ii) wild-type AAV2 Rep proteins, b) an adenoviral helper plasmid, and c) an AAV vector genome plasmid comprising the nucleic acid construct;
3) the absence of an enabling disclosure for treating the cardiac disease or cardiac defect by administering an AAV viral vector particle comprising a nucleic acid construct comprising any sequence other than an expression cassette encoding lncRNA H19; and
4) the absence of an enabling disclosure for treating any cardiac disease or cardiac defect other than pathological cardiac hypertrophy.
These issues were identified by the Office after analysis of the disclosure provided by the specification. The Office has analyzed the specification in direct accordance to the factors outlined in In re Wands, namely 1) the nature of the invention, 2) the state of the prior art, 3) the predictability of the art, 4) the amount of direction or guidance present, and 5) the presence or absence of working examples, and presented detailed scientific reasons supported by publications from the prior art for the finding of a lack of enablement for the scope of the instant methods. The Wands analysis and supporting specific evidence are presented below for each of the identified issues.
As a first (1) issue, the specification does not provide an enabling disclosure for an AAV2 viral vector particle comprising a modified CAP protein comprising an inserted amino acid section comprising the sequence of SEQ ID NO: 1 without additional N-linker AAA or ASA amino acid sequence and C-linker AA amino acid sequence flanking the sequence of SEQ ID NO: 1. The broadest independent claim, claim 1, recites an AAV2 viral vector comprising a nucleic acid construct for an effector molecules, comprising a CAP which C-terminally to amino acid No. 587 of the wild-type amino acid sequence of CAP of SEQ ID NO: 56 contains an inserted amino acid section comprising SEQ ID NO: 1. Claims 2-11 depend upon claim 1 and claim 13 encompasses claim 1. Independent claim 12 recites a process of making an AAV2 viral vector particle having a modified capsid protein with the same structural limitations as the modified capsid protein of independent claim 1.
The disclosure teaches the screening and identification of AAV2 viral vectors comprising inserted amino acid sections comprising a 7-amino acid variable sequence flanked by N-terminal AAA or ASA amino acid residues and C-terminal AA amino acid residues, wherein the 7-amino acid sequence of SEQ ID NO: 1 was identified to have beneficial activity with regards to level of infectivity, antibody reactivity, and tropism [page 7 ¶ 5, Figure 1-6]. The specification does not teach the insertion of SEQ ID NO: 1 in the absence of the indicated N-linker and C-linkers sequences nor in the presence of any other N-linker or C-linker sequences.
The art at the time of filing teaches that achieving greater control and predictability of function of AAV vectors remains a non-trivial task, and that rational design strategies draw from an ever-expanding body of AAV knowledge as a framework for harnessing virus behavior [Lee et al. 2018, Current Opinions in Biomedical Engineering, 7, 58-63, column 4 ¶ 1, column 8 ¶ 2]. Lee further teaches that in consideration of clinical translation, areas that have been explored but still require further progress include improving AAV transduction efficiency, targeting specificity, and minimizing recognition by the host immune system [column 8 ¶ 2]. Lee also teaches that while mutation of various capsid residues may impart desirable characteristics, such as enhanced transduction or specific tissue de-targeting, the precise mechanisms behind these outcomes often remain poorly understood; therefore, additional comprehensive experiments are needed to further understanding of capsid sequence-structure-function relationships [column 8 ¶ 2]. For example, when inserting exogenous motifs into the AAV capsid, Lee teaches that is sometimes difficult to minimize their effects on capsid assembly and hence vector production [column 8 ¶ 2].
Thus, in view of the unpredictable nature of AAV capsid modifications, including AAV capsid insertions, on the function, titer, and tropism of the resultant modified AAV capsid protein, Applicant’s disclosure of only insertions comprising an ASA or AAA N-linker and an AA C-linker flanking the insertion sequence (e.g., the sequence of SEQ ID NO: 1), and the breadth of the claims, the ordinarily skilled artisan would have considered the insertion of the sequence of SEQ ID NO:1 in the absence of the linker sequences present in the functional screen used to identify SEQ ID NO: 1 as an insertion with the desired functional characteristics as highly unpredictable. As such it would have required undue experimentation to practice the scope of Applicant’s invention as claimed.
As a second (2) issue, the specification does not provide an enabling disclosure for a process for producing AAV2 viral vector particles by delivery any components for AAV vector production other than components comprising a) an AAV helper plasmid comprising a nucleic acid sequence encoding i) the modified CAP protein, and ii) wild-type AAV2 Rep proteins, b) an adenoviral helper plasmid, and c) an AAV vector genome plasmid comprising the nucleic acid construct. The broadest independent claim, claim 1, recites an AAV2 viral vector comprising a nucleic acid construct for an effector molecules, comprising a CAP which C-terminally to amino acid No. 587 of the wild-type amino acid sequence of CAP of SEQ ID NO: 56 contains an inserted amino acid section comprising SEQ ID NO: 1. Claims 2-11 depend upon claim 1 and claim 13 encompasses claim 1. Independent claim 12 recites a process of making an AAV2 viral vector particle having a modified capsid protein with the same structural limitations as the modified capsid protein of independent claim 1, wherein the process comprises delivery of components for AAV vector production in a cultivated eukaryotic cell, followed by cell lysis and removal of cellular components and plasmid DNA, and further purification of AAV viral vector particles.
The specification discloses a method of producing AAV2 viral vector particles comprising plasmid transfection into HEK293T cells of all required components for AAV vector production, which include plasmids which express the AAV cap and rep genes, an AAV helper plasmid, and a plasmid comprising the AAV vector genome comprising the transgene expression cassette flanked by ITRs [page 8 ¶ 5-page 9 ¶ 2, page 13 ¶ 3, page 14 ¶ 2, 4].
The art at the time of filing teaches the production of recombinant AAV particles requires helper viruses such as adenovirus, the rep and cap genes, wherein the native viral genome can be replaced with a desired transgene flanked by ITRs, wherein the rep gene encodes four proteins for replication (i.e., Rep78, Rep68, Rep52, and Rep40) and the cap gene encodes the viral capsid proteins VP1, VP2, and VP3 and the non-structural protein AAP [Lee column 1 ¶ 1- column 2 ¶ 2].
Thus, in view of the art recognized requirement for the adenoviral helper genes and the rep and cap genes, along with the viral genome;, Applicant’s disclosure of a process for producing AAV which comprises plasmids comprising the adenoviral helper plasmid, the rep and cap genes, the viral genome; and the scope of the claims, an ordinarily skilled artisan at the time of filing the instant application would have considered producing AAV2 viral vector particles with any components for AAV vector production in any cultivated eukaryotic cell as highly unpredictable. As such it would have required undue experimentation to practice the scope of Applicant’s invention as claimed.
As a third issue (3), the specification does not provide an enabling disclosure for treating the cardiac disease or cardiac defect by administering an AAV viral vector particle comprising a nucleic acid construct comprising any sequence other than an expression cassette encoding lncRNA H19. The broadest independent claim, claim 1, recites an AAV2 viral vector comprising a nucleic acid construct for an effector molecules, comprising a CAP which C-terminally to amino acid No. 587 of the wild-type amino acid sequence of CAP of SEQ ID NO: 56 contains an inserted amino acid section comprising SEQ ID NO: 1. Claims 2-11 depend upon claim 1 and claim 13 encompasses claim 1. Independent claim 12 recites a process of making an AAV2 viral vector particle having a modified capsid protein with the same structural limitations as the modified capsid protein of independent claim 1, wherein the process comprises delivery of components for AAV vector production in a cultivated eukaryotic cell, followed by cell lysis and removal of cellular components and plasmid DNA, and further purification of AAV viral vector particles. Independent claim 13 recites “a method of treatment for a cardiac disease, including cardiac defects, comprising administering the AAV2 vector particle according to claim 1 to a patient who is diagnosed as having the cardiac disease or cardiac defect”.
The specification discloses an example in which AAV2-THGTPAD, which comprises a capsid protein comprising the sequence of elected instant SEQ ID NO: 1 (THGTPAD) inserted between amino acids 587 and 588 according to instant SEQ ID NO: 56, wherein the AAV-THGTPAD viral vector particles comprises a viral genome comprising an expression cassette for lncRNA H19 [page 21 ¶ 2, Figure 1, 7]. The specification further teaches eGFP as an effector gene, but eGFP is merely a fluorescent protein used as a marker for viral transduction with no beneficial functions for the treatment of any cardiac disease or any cardiac disorder [page 15 ¶ 4, Figure 6]. The specification also recites generic language that the effector molecule can be non-coding RNA or a protein-coding RNA and wherein exemplary effector molecules can be selected from any wild-type sequence, including natural genes from any species [page 8-9], but does not disclose any other effector molecule for the treatment of a cardiac disease or cardiac defect.
The art at the time of filing teaches that gene therapy requires the delivery/ targeting of specific genes relevant to the specific disease or disorder being treated [Dunbar et al. 2018, Science, 359 (175), 1-10, Table 2], and that the identification of the molecule pathways involved in the pathophysiology of heart failure and other associated diseases led to encouraging preclinical gene therapy studies which yielded only modest or no improvement in clinical endpoints [Rincon et al. 2015, Cardiovascular Research, 108, 4-20, abstract]. Rincon further teaches that a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure, such as delivery of SERCA2a, which was not shown to be clinically beneficial in a Phase IIb trial, leading to the consideration of alternative targets such as S100A1 and adenylate cyclase 6 [abstract]. Even as late as 2024, the art teaches that gene therapies differ according to the mechanisms and functional consequences of causal genetic variants, such that specific gene constructs are targeted to specific cell types to treat specific conditions requiring genetic understanding, therapeutic innovation, and precise targeting of specific therapeutic genes to specific cardiovascular tissues [Kim et al. 2024, Circulation, 150, e471-480, column 3 ¶ 3, column 12 ¶ 1, Table 1].
Thus, in view of the art-recognized need to specifically tailor gene therapy constructs to the specific condition of a patient, such that the therapeutic gene/ encoded protein (e.g., effector molecule) is particularly relevant to the particular patient, Applicant’s disclosure of only a single specific effector molecule for the treatment of a cardiovascular condition, the lack of predictability of efficacy even for specifically selected targets, and the breadth of the claims, the ordinarily skilled artisan would have considered treating a cardiac disease or cardiac defect by administering an AAV2 viral vector particle comprising a nucleic acid construct comprising any effector molecule as highly unpredictable. As such it would have required undue experimentation to practice the scope of applicant’s invention as claimed.
As a fourth issue (4), the specification does not provide an enabling disclosure for treating any cardiac disease or cardiac defect other than pathological cardiac hypertrophy. The broadest independent claim, claim 1, recites an AAV2 viral vector comprising a nucleic acid construct for an effector molecules, comprising a CAP which C-terminally to amino acid No. 587 of the wild-type amino acid sequence of CAP of SEQ ID NO: 56 contains an inserted amino acid section comprising SEQ ID NO: 1. Claims 2-11 depend upon claim 1 and claim 13 encompasses claim 1. Independent claim 12 recites a process of making an AAV2 viral vector particle having a modified capsid protein with the same structural limitations as the modified capsid protein of independent claim 1, wherein the process comprises delivery of components for AAV vector production in a cultivated eukaryotic cell, followed by cell lysis and removal of cellular components and plasmid DNA, and further purification of AAV viral vector particles. Independent claim 13 recites “a method of treatment for a cardiac disease, including cardiac defects, comprising administering the AAV2 vector particle according to claim 1 to a patient who is diagnosed as having the cardiac disease or cardiac defect”.
The specification discloses an example in which AAV2-THGTPAD, which comprises a capsid protein comprising the sequence of elected instant SEQ ID NO: 1 (THGTPAD) inserted between amino acids 587 and 588 according to instant SEQ ID NO: 56, wherein the AAV2-THGTPAD viral vector particles comprises a viral genome comprising an expression cassette for lncRNA H19 [page 21 ¶ 2, Figure 1, 7]. The specification further teaches the administration of the AAV2-THGTPAD-H19 viral vector particles to a transverse aortic construction (TAC) mouse model, which model is known to exhibit pathologic cardiac hypertrophy, wherein administration of the AAV-THGTPAD-H19 resulted in significant rescue in left ventricular ejection fraction compared to AAV9-H19 and empty vector control groups [page 21 ¶ 2, Figure 7]. The left ventricular ejection fraction improvement was also accompanied by lower left ventricular mass, rescued cardiac dimensions, and lower heart weight to tibia length ratio for the AAV2-THGTPAD-19 compared to AAV9-H19 and empty vector control groups [page 21 ¶ 2, Figure 7]. The specification does not teach the administration of AAV2-THGTPAD-H19, or any other AAV vector particles, for the treatment of any other condition.
The art at the time of filing teaches that lncRNA H19 has varied functions in the heart, contributing differentially to distinct cardiac conditions, wherein H19 is sometimes protective and sometimes contributing to disease development [Gomes et al. 2017, Molecular Therapy: Nucleic Acids, 8, 494-507, column 7 ¶ 3- column 9 ¶ 1, Figure 2, 3, 4]. Even as late as 2022, the art teaches that lncRNA H19 is an attractive candidate as a biomarker and target for therapy due to its importance in cardiovascular homeostasis and disease, and that cardiac-specific overexpression of H19 via vector-based gene therapy ameliorated cardiac dysfunction of TAC-operated mice [Busscher et al. 2022, Clinical Science, 136, 1157-1178, page 1168 ¶ 3, Table 1, Figure 3]. However, Busscher also teaches that down-regulation of H19 expression improved left ventricular function in a different disease model, showing that different insults can lead to different H19 expression patterns, such that with different forms of cardiomyopathies, there might be several distinct downstream pathways leading to differential H19 expression, specific functions, and distinct outcomes [page 1168 ¶ 3].
Thus, in view of the varied roles of H19 expression and varied effects of H19 expression on different cardiac disease phenotypes, Applicant’s sole disclosure of the administration of AAV2-THGTPAD-H19 for the treatment of TAC-induced pathologic cardiac hypertrophy, and the breadth of the claims, the ordinarily skilled artisan would have considered treating any cardiac disease or any cardiac disorder with an AAV2-THGTPAD viral particle expressing lncRNA H19, or any other effector molecule, as highly unpredictable. As such it would have required undue experimentation to practice the scope of Applicant’s invention as claimed.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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, Maria G. Leavitt can be reached on (571) 272-1085. 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.
DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634