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 .
Claim Status
Receipt is acknowledged of the preliminary amendments filed on 20 March, 2024. Claims 2-6, 9-12, 14-16, 18, 21, 25, 26, 28, 30, 31, 36, 37, 39, 40, 44-48, 52, 53, 57, and 59 are amended. Claims 1, 7, 8, 13, 17, 19, 20, 22-24, 27, 29, 32-35, 38, 41, 43, 49-51, 54-56, and 58 are cancelled.
Therefore, claims 2-6, 9-12, 14-16, 18, 21, 25-26, 28, 30-31, 36-37, 39-40, 42, 44-48, 52-53, 57, and 59-61 are pending and under examination in the present Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2022/014091, filed 27 January, 2022, which claims priority to United States Provisional Application Nos. 63/261,603, filed 24 September, 2021, 63/201,466, filed 30 April, 2021, and 63/142,121, filed 27 January, 2021. Acknowledgment is made of applicant’s claim for priority.
The earliest possible priority for the instant application is 27 January, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03 November, 2023, and 20 November, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because some of them are out of focus and illegible. Specifically, FIG. 21-22 are out of focus and small font within the figures is 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 Objections
The claims interchangeably refer to the sequences within SEQ ID NOs. as either a polynucleotide sequence or a nucleic acid sequence. For example, claim 2 refers to “said nucleic acid sequence is at least 85% identical to SEQ ID NO: 238” whereas claim 14 refers to “has the polynucleotide sequence of one of SEQ ID NOs: 84-103”. Please pick one designation and remain consistent throughout the claims. Care should be taken to avoid raising new issues of indefiniteness when amending the claims.
Claims 2-6, 9-11, 39, 42, 44-45, and 60 are objected to because of the following informalities: Because a SEQ ID NO is a placeholder, the claims should be amended to refer to the sequence of a SEQ ID NO, rather than the SEQ ID NO itself. For example: claim 2 should be amended to refer to “identical to the nucleotide sequences of SEQ ID NO: 238, 236, or 243” and to “identical to the amino acid sequence of SEQ ID NO: 181”, claim 5 should be amended to refer to “said C1 inhibitor comprises the amino acid sequence of SEQ ID NO: 181”, claim 10 should be amended to refer to “a nucleic acid sequence” and “said nucleic acid sequence is one of the nucleic acid sequences of SEQ ID NOs: 143-144, 158, and 165-170”, and claim 44 should be amended to refer to “comprises a VP1 comprising the amino acid sequence of SEQ ID NO: 226, a VP2 comprising the amino acid sequence of SEQ ID NO: 189 and a VP3 comprising the amino acid sequence of SEQ ID NO: 190”. It is noted that claim 11 and some others herein objected to refer to “a sequence of SEQ ID NO…”. This language reads on a dinucleotide which appears not to be the intended scope. Appropriate correction is required.
Claim 12 is objected to because of the following informalities: “acid” is misspelled and is currently recited as “acd”. Appropriate correction is required.
Claim 15 is objected to for the following informalities: the claim is missing “of” in between “the polynucleotide” and “claim 14”. Appropriate correction is required.
Claims 28 and 31 are objected to because of the following informalities: abbreviations/acronyms must be spelled out upon their first encounter in the claims (for example: “WPRE3”, “WPRE”, and “UTR”). Appropriate correction is required.
Claim 30 is objected to because of the following informalities: the claim should refer to the SEQ ID NOs in the alternative because the claim recites “one of SEQ ID NOs”. Appropriate correction is required.
Claim 39 is objected to because of the following informalities: “91” was not crossed out at the end of the claim with the last amendment. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 57 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The term “cells” defined by the specification at page 18, line 3-12 states that the cell is in vitro or in vivo. The scope of the claims, therefore encompasses a human being, which is non-statutory subject matter. As such, the recitation of the limitation “non-human” or “isolated” would be remedial. See 1077 O.G. 24, April 21, 1987.
Claim Rejections - 35 USC § 112
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.
Claim 6, 9, 11, 12, 14-16, 18, 21, 25-26, 28, 30-31, 36-37, 39-40, 42, 44-48, 52-53, 57, and 59 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 depends from claim 5 and recites “the polynucleotide further comprises a signal peptide at the 5’ end of said nucleic acid sequence”. This language is indefinite because it is unclear whether Applicant intends the scope of the claim to encompass some sort of nucleic acid/polypeptide hybrid molecule or whether Applicant instead intends the claim to encompass a nucleic acid sequence encoding a signal peptide sequence at the 5’ end of said nucleic acid sequence.
Claim 9 recites the limitation "the nucleic acid" in the first line of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 2 from which claim 9 depends does not recite “a nucleic acid”. Rather, claim 2 recites “A polynucleotide comprising a nucleic acid sequence”. Therefore, there is insufficient antecedent basis for “the nucleic acid”. Further, claim 9 recites “the nucleic acid has a polynucleotide sequence” which is confusing if claim 9 is attempting to refer back to “a nucleic acid sequence” because “a nucleic acid sequence” as recited in claim 2 is comprised by “a polynucleotide”. It is recommended to amend claim 9 to instead recite “The polynucleotide of claim 2, wherein the nucleic acid sequence is any one of the nucleic sequences of SEQ ID NOs: 105-142, 145-147, 156, 171 and 172.”
Claim 11 recites the limitation "said nucleic acid" in the second line of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 2 from which claim 11 depends does not recite “a nucleic acid”. Rather, claim 2 recites “A polynucleotide comprising a nucleic acid sequence”. Therefore, there is insufficient antecedent basis for “said nucleic acid”. Further, claim 11 is indefinite in its recitation of “the amino acid sequence of 192”. If Applicant intends to reference a SEQ ID NO, then they should recite SEQ ID NO: 192 accordingly. Otherwise and as written, no such reference is made and claim 11 is indefinite because the metes and bounds of the claim cannot be determined.
Claim 12 is indefinite in its recitation of “a nucleic acid encoding a signal peptide sequence”. A nucleic acid does not encode anything in itself. Rather, a sequence of nucleic acids is what encodes a polypeptide via a minimum of 3 nucleic acids per amino acid encoded. Therefore, it is unclear how “a nucleic acid” can encode anything by itself and claim 12 is indefinite because of this lack of clarity. Further, claim 2 from which claim 12 ultimately depends already recites “a nucleic acid sequence”. Applicant should take care to amend claim 12 to recite “a second nucleic acid sequence” in overcoming this rejection so as to not raise new issues of indefiniteness.
Claim 14 recites the limitation "the polynucleotide acid" in the first line of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 14 depends from claim 12 which ultimately depends from independent claim 2. Nowhere in the dependency is there a recitation of “a polynucleotide acid”. Rather, claim 2 from which claim 14 ultimately depends recites “a polynucleotide”.
Claim 15 recites the limitation "said expression element" in the second and third lines of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 15 recites “an expression control element” and nowhere in claim 15 is there a recitation of “an expression element”.
Claim 16 recites the limitation "said nucleic acid encoding the C1 inhibitor" in the second and third lines of the claim. There is insufficient antecedent basis for this limitation in the claim. Nowhere in the chain of dependency between claim 16 and claim 2 from which claim 16 ultimately depends is there a recitation of “a nucleic acid encoding the C1 inhibitor”. Rather, claim 2 recites “a nucleic acid sequence encoding a C1 inhibitor”.
Claim 18 is confusing as written. Claim 18 recites “an ApoE/hAAT enhancer/promoter sequence”. This recitation is confusing because it is unclear whether Applicant intends the scope of claim 18 to encompass an ApoE enhancer sequence and a hAAT promoter sequence or instead an ApoE, a hAAT enhancer, and a promoter. Both the former and the latter readings are further confusing insofar as the ApoE gene is commonly understood as a gene which contains a promoter and enhancer elements while hAAT is commonly understood as a promoter. Thus, claim 18 is indefinite for being confusing as written and the metes and bounds cannot be determined.
Claim 21 recites the limitation "said ApoE enhancer" and “said hAAT promoter” in the second and third lines of the claim respectively. There is insufficient antecedent basis for these limitations in the claim. Claim 18 from which claim 21 depends does not recite an ApoE enhancer and a hAAT promoter. Rather, claim 18 recites “an ApoE/hAAT enhancer/promoter sequence”.
Claim 25 is indefinite in its recitation of “a human hemoglobin β (HBB)-derived intron”. The claim is vague and indefinite in that the metes and bounds of the term “derived from” are unclear. It is unclear the nature and number of steps required to obtained a “derivative” of. The term implies a number of different steps that may or may not result in a change in the functional characteristics of from the source that it is “derived from”. Further, it is unclear how much similarity an intron must have to an intron of HBB to be considered HBB-derived. Thus, a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought in claim 25.
Claim 28 is unclear in its recitation of “hAAT”. hAAT is commonly understood as a promoter not an enhancer. Thus, claim 28 is unclear insofar as it refers to hAAT as an enhancer.
Claim 30 is confusing in its recitation of “one of SEQ ID NOs: 225 and 74-78 and 173-178”. It is confusing because the claim is referring to “one of” then reciting a list not in the alternative. A person having ordinary skill in the art would not be apprised of the scope of claim 30 insofar as they would be unsure whether the claim encompasses one of the recited groupings or one of the individual sequences of the SEQ ID NOs.
Claims 36 and 37 are confusing in their recitation of “AAV vector”. If AAV vector is referring to a viral particle, then claim 37 is inherent but if AAV vector is referring to a nucleic acid vector, then it is unclear how a nucleic acid vector can comprise an AAV capsid which is itself a polypeptide molecule. Thus, the metes and bounds of claims 36 and 37 are confusing as written and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claim 39 recites “having 95% or more sequence identity to AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, Rh10, Rh74 (SEQ ID NO: 188), AAV3B, AAV-2i8, SEQ ID NO: 226, SEQ ID NO: 189, SEQ ID NO: 190, and/or SEQ ID NO: 191”. This recitation is indefinite because (1) it is unclear how a VP1, VP2, and/or VP3 can in themselves be 95% or more identical to a particular serotype of AAV (they can clearly be 95% or more identical to a VP1, VP2, and/or VP3 of a particular serotype of AAV but not to the AAV serotype itself), (2) it is unclear whether the SEQ ID NO in the parenthetical is intended to be encompassed by the claim or whether it is merely provided as exemplary, and (3) it is unclear how “a modified or variant AAV VP1, VP2, and/or VP3” can comprise any or all of the recited species (AAV1, AAV2, AAV3, etc.) (please replace “and/or” with “or”).
Claim 44 recites the limitation "said capsid" in the first line of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 36 from which claim 44 ultimately depends does not recite a capsid nor does claim 44 itself or any claim within the dependency chain between claim 44 and 36.
Claim 45 is indefinite in its recitation of “said polynucleotide” followed by “SEQ ID NO: 22”. Claim 42 from which claim 45 depends recites “a polynucleotide sequence…consisting of SEQ ID NOs: 1-69”. Claim 2 from which claim 45 ultimately depends recites “a polynucleotide comprising a nucleic acid sequence…” without reciting any of SEQ ID NOs: 1-69. Thus, claim 45 technically refers back to the antecedent in claim 2 while reciting a SEQ ID NO (SEQ ID NO: 22) which claim 42 defines as being comprised in “a polynucleotide sequence” (a separate antecedent). Consequently, it is unclear which antecedent claim 45 is referring to and the claim is indefinite. The same issue is presented in claim 46. Therefore, claim 46 is also rejected for being indefinite on the same grounds.
Claims 14-16, 18, 21, 25-26, 28, 30-31, 36-37, 39-40, 42, 44-48, 52-53, 57, and 59 are further rejected for their dependency on a rejected base claim.
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 40 is 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 40 recites “one or more ITRs”. Claim 37 from which claim 40 ultimately depends requires “AAV inverted repeats (ITRs) flanking the 5’ and 3’ terminus of the expression cassette”. Thus, claim 37 requires at least two ITRs whereas claim 40 allows for there to only be one ITR. 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.
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 52-53 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 a method of decreasing plasma levels of bradykinin in a mouse, comprising intravenously administering to the mouse 1x1012 to 1x1013 vector genomes per kilogram (vg/kg) of an AAV vector comprising the polynucleotide sequence of SEQ ID NO: 20 or SEQ ID NO: 22, wherein the C1 inhibitor is expressed in the mouse, does not reasonably provide enablement for a method of treating any subject comprising administering to the subject any amount of the AAV vector of claim 37. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. Instant claims 52-53 are drawn to a method of treating a subject in need of a C1 inhibitor comprising administering an AAV vector encoding a C1 inhibitor.
2) Scope of the invention. The scope of the invention is broad insofar as it requires a method of treating any subject comprising administering to the subject any amount of the AAV vector of claim 37. The vector of claim 37 requires the expression cassette of claim 16, any AAV capsid, and any AAV ITRs. The expression cassette of claim 16 requires any promoter operably linked to the polynucleotide of claim 14 and any polyadenylation signal operably linked to the 3’ end of “said nucleic acid encoding the C1 inhibitor”. As discussed above, this recitation in claim 16 is indefinite. Thus, claims 52-53 comprise a method of treating any subject comprising administering to the subject any amount of an AAV vector comprising any AAV capsid, any AAV ITRs, and an expression cassette which itself comprises any promoter and any polyadenylation signal. It is noted that claim 46 specifies a polynucleotide sequence which possess a specific promoter, enhancer, polyadenylation signal, AAV ITRs, AAV capsid gene, and C1 inhibitor gene sequence (See Specification, Table 1). This note is intended to draw Applicant’s attention to scope-limiting measures which can be taken by altering dependency but not which will overcome this rejection in its entirety.
3) Number of working examples and guidance. The specification teaches a list of 69 different SERPING1 expression cassettes (Specification, Table 1). Every one of these 69 expression cassettes possesses an ApoE enhancer element, a hAAT promoter, and a BGH228 polyadenylation signal (Specification, Table 1). The working examples teach that some of the expression cassettes further contain a human hemoglobin subunit beta (HBB2) intron (Specification, [0361]). The working examples also teach that the expression cassettes are packaged in an AAV viral particle by being encapsidated in an AAV capsid “e.g., AAV-4-1 capsid variant” or “LK03 capsid variant” (Specification, [0362]). The working examples specifically teach that AAV-encapsidated SEQ ID NO: 20 and 22 injected into wild type mice at 1x1012vg/kg significantly reduce bradykinin levels in plasma (Specification, Table 6, [0388]) and that administration of AAV-4-1-encapsidated SEQ ID NO: 20 at doses of 4x1012 and 1x1013 vg/kg restores circulating levels of C1 inhibitor in C1 inhibitor knockout mice (Specification, [0396], [0411]). Thus, in terms of the AAV vectors exemplified by the working examples, the only AAV vectors taught which present a measurable endpoint other than mere expression of the transgene are AAV-4-1 encapsidated either SEQ ID NO: 20 or 22 which themselves possess a codon optimized SERPING1, an ApoE enhancer, a hAAT promoter, a modified human hemoglobin R-derived synthetic intron (HBB2), and a CpG-reduced bovine growth hormone polyadenylation signal and whose administration to mice at between 1x1012vg/kg and 1x1013vg/kg results in reduced bradykinin levels (Specification, [0396]).
4) State of the art. Methods of administering AAV comprising the genetic sequence of the normal human C1-esterase inhibitor to a mouse model of hereditary angioedema (HAE) are known in the art (Qiu, et al. Allergy 74.6 (2019): 1081-1089., hereinafter “Qiu”). Qui teaches that such a method in mice can result in abrogation of the increased vascular permeability phenotype associated with HAE and that the goal is to translate their findings to human clinical trials (Qiu, page 7, second full paragraph). However, contemporary treatments for hereditary angioedema caused by C1-esterase inhibitor deficiency are not AAV-based gene therapies but rather can be antisense oligonucleotide or CRISPR-based treatments, C1-esterase inhibitor concentrates, kallikrein inhibitors, or factor-XII inhibitors (Mannucci, et al. eLS 3: 1-7. (2024). Hereinafter “Mannucci”; Johnson, et al. Frontiers in Immunology 16 (2025): 1681763. Hereinafter “Johnson”). The art does not teach a subject in need of C1-esterase inhibitor other than individuals with HAE who are C1-esterase inhibitor deficient. Thus, the state of the art is nascent with regard to the use of AAV-mediated gene therapies for treating individuals in need of C1-esterase inhibitors. Where the art teach treatments for humans, it is a treatment for HAE and it is not AAV-mediated gene therapy.
5) Unpredictability of the art. As discussed directly above, the state of the art for the administration of AAV encoding a C1-esterase inhibitor to individuals in need of a C1-esterase inhibitor is developed in mouse models of HAE but is nascent with regard to human applications. Indeed, Qiu acknowledges a desire to translate their findings to the clinic (Qiu, page 7, second full paragraph) but at the time of filing, existing treatments in humans did not encompass AAV-mediated therapies for HAE (See Johnson and Mannucci). Further, while Applicants have assessed bradykinin levels as a function of C1 inhibitor administration in mice, Qiu used an entirely different endpoint, vascular permeability, for their assessment (See Qiu, Figures 1-4). A skilled artisan viewing the art at the time of filing would have very little guidance in the evaluation of AAV-delivered C1 inhibitors for their therapeutic effect and whether reduction in bradykinin in a mouse model of HAE results in a treatment of any subject is far from predictable. In addition, the method of Qiu used a specific AAVrh10hC1E1 vector comprised of a nonhuman primate-derived rh.10 capsid pseudotyped with AAV2 ITRs surrounding an expression cassette which itself comprised a CMV enhancer, a CAG promoter, the human C1E1 coding sequence, and a rabbit beta globin polyadenylation signal (Qiu, page 4, “AAV Vectors”). The method of Qiu also utilized intravenous administration of the AAV to the mice (Qiu, page 5, first partial paragraph). The method of Qiu used a distinct AAV vector with no components in common with Applicants (including the C1EI gene sequence), assessed distinct endpoints from that of Applicants, and utilized only intravenous administration. In such a nascent field, a skilled artisan at the time of filing would expect the results of using an entirely different AAV vector with entirely different components to be unpredictable at least insofar as they relate to a method of treatment for subjects other than mice and encompassing administration routes other than intravenous administration which is the only route taught in the art at the time of filing for such methods.
At the time of filing, examples other than that of Qiu for AAV-mediated C1-esterase inhibitor administration are sparse in the art. Thus, guidance for the practice of the invention must come substantially from the instant specification. While Applicant’s claims encompass a broad swathe of AAV vectors, they only exemplify two sequences which had a measurable endpoint (SEQ ID NO: 20 and 22). Between these sequences, all components of the vectors are taught as identical with the exception of the specific version of SERPING1 and the specific signal peptide used (Specification, table 1). The only dose range taught for these examples is 1x1012 to 1x1013 vg/kg and the only AAV taught is AAV-4-1 (See above). Further, Applicants only teach intravenous administration (Specification, [0395]) and Applicants only teach a reduction in bradykinin following administration of the AAV vectors to a mouse model of HAE (Specification, [0416]). Applicants don’t even teach a reduction in bradykinin for SEQ ID NO: 20 but they do teach that C1 inhibitor isolated from the plasma of mice which received SEQ ID NO: 20 had the predicted biological activity (Specification, [0405]). Because Applicants have only taught intravenous administration of AAV encapsidated SEQ ID NO: 20 or 22 to mice resulting in bradykinin reduction or sustained biological activity, and because the art at the time of filing is sparse and only teaches a very specific and distinct example in mice relying on distinct endpoints, the skilled artisan would understand there to be unpredictability outside of the specific methods taught in the working examples.
6) Amount of Experimentation Required. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention.
Consequently, the prior art (and post-filing art) when combined with the lack of any disclosed experimental test of methods of treatment and the limitation of the working examples to a method for reducing plasma bradykinin levels in mice comprising intravenously administering 1x1012 to 1x1013 vg/kg AAV-4-1 encapsidated SEQ ID NO: 20 or 22, shows that one of skill in the art at the time the invention was made would have had no basis to reasonably predict or conclude the claimed methods of treatment could be identified for all possible subjects, routes of administration, AAV serotypes, and expression cassettes. Though not controlling, the lack of working examples, is, nevertheless, a factor to be considered. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
Given the very specific method taught in the art relative to the very broad methods that are claimed, the level of unpredictability embodied by the species encompassed by the genus claimed, and the amount of experimentation required to determine the operable species, it would require undue experimentation to use the invention commensurate in scope with the claims.
Claims 2-4, 39, and 40 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 contain 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 broadly directed to a genus of amino acid sequences having at least 95% identity to SEQ ID NO: 181. The apparent function of the polypeptide encoded by SEQ ID NO: 181 is as an inhibitor of C1 protein. It is noted that Applicants are claiming an undefined number of polypeptides having 95% sequence identity with SEQ ID NO: 181. It is also noted that the claims broadly encompass a C1 inhibitor where 24 out of the 478 amino acids of SEQ ID NO: 181 are replaced with any amino acid (including bend-introducing residues like proline and residues containing large aliphatic side chains like tryptophan) while still retaining inhibitory function. There is no structure/function relationship taught at all for SEQ ID NO: 181 (no claimed sequence within SEQ ID NO: 181 which must be conserved to retain inhibitory function). Instant claim 39 is drawn to “a modified or variant AAV VP1, VP2, and/or VP3 having 95% or more sequence identity to AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, Rh10, Rh74 (SEQ ID NO: 188), AAV3B, AAV-2i8, SEQ ID NO: 226, SEQ ID NO: 189, SEQ ID NO: 190, and/or SEQ ID NO: 191”. As discussed above, this language is indefinite in the second recitation of “and/or”. Still further, this language encompasses a vast genus of VP1, VP2, and/or VP3 proteins which have 95% identity to an assortment of different AAV serotypes which are not recited by reference to a specific sequence. Therefore, the true breadth of claim 39 cannot be determined as it encompasses vast numbers of variants of the recited AAV serotypes known or yet to be discovered. For example: If an AAV can be properly designated as “AAV1” yet said AAV possesses an undefined number of modifications, said AAV would fall within the scope of claim 39. Instant claim 40 is drawn to an AAV vector having “one or more” ITRs of any of a list of AAV serotypes “or a combination thereof”. Thus, claim 40 encompasses a vast genus of AAV vectors having only a single ITR (yet still able to assemble into an AAV vector) wherein said single ITR is “a combination” of “AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, Rh10, Rh74, AAV3B, AAV serotypes”. In the last listed limitation of claim 40, it appears to encompass any and all AAV serotypes known and yet to be discovered.
There is no disclosure in the instant specification of what residues within SEQ ID NO: 181 are critical for the retention of inhibitory function. The instant specification discloses that SEQ ID NO: 181 is mature C1 inhibitor while SEQ ID NO: 192 is that same C1 inhibitor with a signal peptide (Specification, [0010]). The instant specification also discloses that the nucleic acid of the instant invention encodes either SEQ ID NO: 181 or 192 or a C1 inhibitor having 93% identity to SEQ ID NO: 181 (Specification, [0121], [0136], [0356]). As discussed in the above enablement rejection, Applicants only exemplify two sequences which had a measurable endpoint which can be correlated to retained inhibitory function (SEQ ID NO: 20 and 22). Between these sequences, all components of the vectors are taught as identical with the exception of the specific version of SERPING1 and the specific signal peptide used
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(Specification, table 1). SEQ ID NO: 20 possesses SEQ ID NO: 236 while SEQ ID NO: 22 possesses SEQ ID NO: 238 (Specification, table 1). Both of SEQ ID NO: 236 and 238 encode the same amino acid sequence and that amino acid sequence is SEQ ID NO: 181 (see above). Therefore, the specification only teaches a single C1 inhibitor amino acid sequence which possesses the function of an inhibitor (SEQ ID NO: 181). Further, The specification only teaches working examples with an AAV-4-1 encapsidated sequence (see above enablement rejection). Still further, the working examples only teach expression cassettes having two ITRs (Specification, [0361]). The working examples do not specify which ITRs were used but the specification teaches that AAV2 ITRs are utilized in preferred embodiments (Specification, [0035]-[0044]). This comports with the teachings of Qiu which provide for the use of AAV2 ITRs to deliver C1 inhibitor to a mouse (Qiu, page 4, “AAV Vectors”).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). Further, A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See MPEP 2163(II)(A)(3)(a)(ii).
In disclosing only a single amino acid sequence which possesses the function of an inhibitor (SEQ ID NO: 181), applicant has not disclosed a representative number of species for the entire genus claimed because the genus claimed covers species in which SEQ ID NO: 181 has as many as 24 out of the 478 amino acids of SEQ ID NO: 181 are replaced with any amino acid (including bend-introducing residues like proline and residues containing large aliphatic side chains like tryptophan). Hence, the structure/function correlation of a polypeptide is unpredictable, and a skilled artisan would recognize that the vast genus claimed as elected encompasses C1 inhibitors whose inhibitory function would be hindered if not abolished by specific amino acid substitutions.
The skilled artisan understands that one nucleotide change in a DNA molecule or one amino acid change in the polypeptide encodes by the DNA molecule could result in loss of it’s biological activity as demonstrated in the generation of sickle-cell anemia wherein one specific amino acid mutation gives rise to the inherited disease (Voet et al., Biochemistry, John Wiley and Sons, 1990, p. 126-129). Further, the skilled artisan also understands that the significance of particular amino acids within a peptide cannot be predicted a priori but must be determined from case to case by painstaking experimental study (Rudinger, J., Peptide Hormones. Palgrave, London, 1976. 1-7. (Page 6, “Conclusions”)) and that it is not known whether there exists an algorithm for predicting the structure of a given protein from its amino acid sequence alone (Ngo, et al., The protein folding problem and tertiary structure prediction. Boston, MA: Birkhäuser Boston, 1994. 433-506. (page 492, second full paragraph)). The specification prophetically suggests that C1 inhibitors possessing an amino acid sequence 95% identical to SEQ ID NO: 181 can be used to practice the invention (Specification, [0356]). However, only SEQ ID NO: 181 itself is disclosed as having the functional activity of inhibition, which is not predictive of any mutation or combination of mutations which may be introduced to SEQ ID NO: 181 to accomplish inhibition. Thus, a skilled artisan would understand from the teachings of Voet, Rudinger, and Ngo that the results of changing any given amino acid within SEQ ID NO: 181 would be unpredictable and that it would require significant experimentation to determine which variants of SEQ ID NO: 181 would still possess the desired function.
The claims encompass sequences 95% identical to the full length of SEQ ID NO: 181, SEQ ID NO: 181 is 478 amino acids long. That 5 percent variance results in a situation in which if a 24-contiguous amino acid region within SEQ ID NO: 181 were independently varied among the 20 different naturally occurring amino acids, there would be 1.67 x 1031 (2024 ) different possible molecules. In fact, since variations could occur anywhere within SEQ ID NO: 181, the actual number of different molecules encompassed by the claims as elected is orders of magnitude higher than 2024. Computer software may provide means for identification of such element, but it is not itself an adequate written description of the structure of the claimed invention. Further, no reference sequence is even provided for a majority of the AAV serotypes listed in claim 39, therefore, the number of different variants claimed is undefined and cannot be even calculated in a hypothetical. Thus, Applicant has not disclosed a representative number of species for the entire genera of sequences, AAV capsid proteins, and ITRs claimed.
Additional Comments
Claims 5-6, and 60-61 are indicated as free of the prior art of record. The entirety of the prior art of record does not provide substantial evidence to teach, suggest, or motivate a person having ordinary skill in the art to make a nucleic acid sequence that is at least 97% identical to SEQ ID NO: 238, or a polypeptide comprising a sequence that is at least 95% identical to any one of SEQ ID NOs: 215, 216, 217, and 218.
Conclusion
Claims 2-4, 6, 9-12, 14-16, 18, 21, 25-26, 28, 30-31, 36-37, 39-40, 42, 44-48, 52-53, 57, and 59 are rejected. Claim 5 is objected to but is otherwise allowable. Claim 60 is objected to, claim 61 depends from claim 60, claims 60-61 are otherwise allowable.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA MARVICH/Primary Examiner, Art Unit 1634