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
Applicant’s amendments and remarks, filed 09/03/2025, are acknowledged.
Claims 2-4, 7, 12, 14-15, 17, 19-23, 26, 28-29, 31-43, and 45 are canceled.
Claims 1, 5-6, 9-11, 16, 18, 24-25, 27, 30, and 44 are amended.
Claims 46-48 are new.
Claims 1, 5-6, 8-11, 13, 16, 18, 24-25, 27, 30, 44, and 46-48 are pending.
Claims 24-25, 27, and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 03/25/2024.
As such, claims 1, 5-6, 8-11, 13, 16, 18, 44, and 46-48 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/03/2025 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/04/2025 was filed after the mailing date of the final Office action on 03/03/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 09/03/2025.
The specification objections are withdrawn. Issues regarding minor informalities and trademarks/names have been sufficiently addressed through amendments to the specification on 09/03/2025.
Withdrawn Rejections
Applicant’s arguments, see pages 21-22 and 24-31, filed 09/03/2025, with respect to claims 1, 3, 5-6, 8-11, 13-14, 16-18, and 44 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Further, Examiner acknowledges that claims 3, 14, and 17 are canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(b) is withdrawn.
Applicant’s arguments, see pages 37-44, filed 09/03/2025, with respect to claims 1, 3, 5-6, 8-11, 13-14, 16-18, and 44 rejected under 35 USC 112(a) as allegedly lacking of enablement have been fully considered and are persuasive. The issue regarding the specification failing to disclose that the specification is enabling for a method of modulating the expression and/or activity of MPO in all mammals with all gene editing compounds and all undifferentiated BM cells nor a method for treating, ameliorating, inhibiting or delaying the onset of any MPO-related condition or disorder, or NETosis and related conditions, in all mammals, with all gene editing compounds in any undifferentiated BM cell of said subject, any nucleic acid molecule comprising a sequence encoding said gene editing compound, any composition, or vehicle comprising said at least one gene editing compound; and (b) any undifferentiated BM cell or cell population exhibiting a modulated expression and/or activity of MPO been sufficiently addressed through amendments to the claims. Specifically, Examiner acknowledges that the base claims were amended to specifically recite specific conditions or disorders. Further, Examiner acknowledges that claims 3, 14, and 17 are canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(a) is withdrawn.
Applicant’s remarks, see pages 44-49, filed on 09/03/2025, with respect to claims 1, 3, 6, 9-11, 14, 17-18, and 44 rejected under 35 USC 102 as allegedly anticipated by Zhang et al (US 2016/0175462 A1, pub. 06/23/2016) have been fully considered and are persuasive. Examiner acknowledges that claims 3, 14, and 17 are canceled, thus rendering the rejection moot. Further, Examiner acknowledges that the claims were amended to recite reducing MPO expression and/or activity in a mammalian subject affected by or suffering from at least one MPO-related condition or disorder comprising administering an effective amount of at least one of: (a) at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated BM, and (b) at least one undifferentiated BM cell or undifferentiated BM cell population exhibiting reduced or inhibited expression and/or activity of MPO which is not disclosed by Zhang et al. As such, the rejection of claims 1, 6, 9-11, 18, and 44 under 35 USC 102 is withdrawn.
Claim Objections
Claims 1, 6, and 46 are objected to because of the following informalities:
Claims 1 and 6: “CRISPER/Cas system” should read “CRISPR/Cas system”.
Claim 46 does not end with a period. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Appropriate correction is required.
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, 5-6, 8-11, 13, 16, 18, 44, and 46-48 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.
Claims 1 and 10 recite “AVV” as an acronym for ANCA-associated vasculitis; however, the specification recites “AVV” and “AAV” as acronyms for this condition (see pages 58-60) and “AAV” for adeno associated vectors (see pages 24 and 25), thus it is unclear what acronym Applicant is using for ANCA-associated vasculitis. As such, the claims 1 and 10, and their dependent claims, are rejected.
Claim 5 recites the limitation "said gRNA" in lines 1 and 2. There is insufficient antecedent basis for this limitation in the claim.
Claims 6(i), 11(i), and 13 recite “one undifferentiated BM cell or a BM cell population”. It is unclear whether the “BM cell population” is also undifferentiated, or if the singular BM cell is solely undifferentiated.
Claims 10, 44, and 48 recite “a nucleic acid molecule encoding said Cas protein, or a nucleic acid construct comprising said nucleic acid sequence”. It is unclear if the “said nucleic acid sequence” within the nucleic acid construct is referring to the “nucleic acid molecule” mentioned prior, or if the claim is referencing a different sequence. As such, claims 10, 44, and 48, and their dependent claims are rejected.
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 1, 6, 8-11, 13, 18, 44, and 47-48 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 claim(s) 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 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a method of reducing the expression and/or activity of Myeloperoxidase (MPO) in a mammalian subject, the method comprising the step of administering to said subject an effective amount of at least one of: (a) at least one clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR associated (cas) protein system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated bone marrow (BM) cell of said subject, said CRISPR/Cas system comprising at least one of: clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR associated (cas) protein system; and (b) at least one undifferentiated BM cell or undifferentiated BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO; wherein said subject is a subject affected by or suffering from at least one MPO-related condition or disorder selected from the group consisting of: Alzheimer's disease (AD), multiple sclerosis (MS), Pulmonary arterial hypertension (PAH), Antineutrophil cytoplasmic autoantibody (ANCA)-Associated Vasculitis (AVV) and ANCA-associated glomerulonephritis (AAGN).
Claim 6 is drawn to the method according to claim 1, wherein at least one of: (i) said at least one undifferentiated BM cell or undifferentiated BM cell population is at least one undifferentiated BM cell or a BM cell population transduced or transfected with said at least one said CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in said cells; (ii) the at least one undifferentiated BM cell or the undifferentiated BM cell population is of an autologous or of an allogenic source.
Claim 8 is drawn to the method according to claim 1, wherein said undifferentiated BM cell population is a BM cell population of an allogeneic subject exhibiting an inhibited or eliminated expression and/or activity of MPO.
Claim 9 is drawn to the method according to claim 1, wherein reducing the expression and/or activity of MPO comprises inhibiting or eliminating the expression and/or activity of MPO in said subject.
Claim 10 is drawn to the method according to claim 1, for treating, ameliorating, inhibiting or delaying the onset of an MPO-related condition in a mammalian subject, said method comprises the step of administering to said subject a therapeutically effective amount of at least one of: (A) at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated BM cell of said subject; said CRISPR/Cas system comprising at least one of:(i) at least one CRISPR/cas protein; and at least one gRNA that targets a protospacer within the MPO gene:(ii) a nucleic acid molecule encoding said Cas protein, or a nucleic acid construct comprising said nucleic acid sequence; and a nucleic acid sequence encoding said gRNA or a nucleic acid construct comprising said nucleic acid sequence; and (iii) a composition comprising (i) or (ii); and (B) at least one undifferentiated BM cell or undifferentiated BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO; wherein said MPO-related condition or disorder is selected from the group consisting of: AD, MS, PAH, AVV and AAGN.
Claim 11 is drawn to the method according to claim 10, wherein at least of: (i) said at least one undifferentiated BM cell or undifferentiated BM cell population is at least one undifferentiated BM cell or a BM cell population transduced or transfected with said at least CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in said cells; and (ii) the at least one undifferentiated BM cell or undifferentiated BM cell population is of an autologous or of an allogenic source.
Claim 13 is drawn to the method according to claim 10, wherein said at least one undifferentiated BM cell or undifferentiated BM cell population is at least one undifferentiated BM cell or a BM cell population of an allogeneic subject exhibiting an inhibited or eliminated expression and/or activity of MPO.
Claim 18 is drawn to the method according to claim 10, wherein at least one of: (a) said disorder is Alzheimer's disease (AD); (b) said disorder is multiple sclerosis (MS); and (c) said disorder is Pulmonary arterial hypertension (PAH).
Claim 44 is drawn a method for inhibiting neutrophil extracellular trap (NET) activation and release (NETosis) in a mammalian subject, said method comprising the step of administering to said subject a therapeutically effective amount of at least one of: (a) at least CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated BM cell of said subject; and (b) at least one undifferentiated BM cell or undifferentiated BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO, wherein said CRISPR/cas system comprising at least one of: (i) at least one CRISPR/cas protein and at least one gRNA that targets a protospacer within the MPO gene: (ii) a nucleic acid molecule encoding said Cas protein, or a nucleic acid construct comprising said nucleic acid sequence; and a nucleic acid sequence encoding said gRNA or a nucleic acid construct comprising said nucleic acid sequence; and(iii) a composition comprising (i) or (ii).
Claim 47 is drawn to the method according to claim 44, wherein said undifferentiated BM cell population is a BM cell population of an allogeneic subject exhibiting an inhibited or eliminated expression and/or activity of MPO.
Claim 48 is drawn to a method for inhibiting production of reactive oxygen species (ROS) in a mammalian subject, said method comprising the step of administering to said subject a therapeutically effective amount of at least one of: (a) at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated BM cell of said subject; and (b) at least one undifferentiated BM cell or undifferentiated BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO, wherein said CRISPR/cas system comprising at least one of:(i) at least one CRISPR/cas protein; and at least one gRNA that targets a protospacer within the MPO gene; (ii) a nucleic acid molecule encoding said Cas protein, or a nucleic acid construct comprising said nucleic acid sequence; and a nucleic acid sequence encoding said gRNA or a nucleic acid construct comprising said nucleic acid sequence; and(iii) a composition comprising (i) or (ii).
The specification discloses of targeting MPO in the experimental allergic encephalomyelitis (EAE) model of MS (see Example 1). The specification disclose that Lin-hematopoietic progenitors retain their hematopoietic reconstitution potential and are adequate for CRISPR-Cas9 KO experiments (see pg. 95). The specification also discloses of targeting MPO in the FAD model of Alzheimer disease (AD) (see Example 2). The specification discloses that blood samples from FAD model mice subjected to transplantation of BM cells obtained from MPO KO mice showed less peroxidase activity, confirming MPO KO hematopoietic reconstitution of MPO KO cells in these mice (see pg. 96, Figs. 3E-3F). Further, almost undetectable MPO-mRNA levels were found in BM derived from wildtype-MPO KO and 5XFAD-MPO KO mice, as compared to high levels in the controls indicating for efficient exchange of the hematopoietic population in the transplanted mice (see pg. 97, Fig. 4B). Example 3 discloses MPO knock-out using CRISPR/Cas9 technology in isolated HSCs (see pgs. 99-101). Example 4 discloses MPO knock-out using CRISPR/Cas9 technology in human cells (HEK293); specifically, discloses transfecting HEK293 cells with ribonucleoproteins (RNP) complexes containing Cas9 protein, fluorescently labeled tracrRNA and crRNA sequences that target the human MPO encoding sequences and the corresponding protospacers: T173 (denoted by SEQ ID NO: 33 and SEQ ID NO: 43, respectively), D260 (denoted by SEQ ID NO: 34 and SEQ ID NO: 44, respectively), H502 (denoted by SEQ ID NO: 35 and SEQ ID NO: 45, respectively), C319 (denoted by SEQ ID NO: 42 and SEQ ID NO: 46, respectively). The specification discloses of using the CRISPR/Cas9 system for manipulating human MPO function and levels (see Example 5). Specifically, Example 5 disclose of the following amino acid substitutions that: form conformational changes in the MPO protein or changes in protomer biosynthesis and processing – C167A, C180A, C319A, C158A, R128A, N355A; mimic human MPO deficiency substitutions – T173C, M251T, R569W, R499C, G501S; interfere with promoter heme binding – Q257A, D260A, M409A, E408A, H261A, H502A; and, interfere with proper protein glycosylation – N355A (see pg. 103). Example 6 discloses of a procedure for a clinical study highlighting hematopoietic stem cell transplantation (HSCT) combined with CRISPR-mediated gene editing. Example 7 discloses of a proposed treatment of PAH using MPO knock-out. Lastly, Example 8 discloses of a proposed treatment of crescentic glomerulonephritis (CGN) using MPO knock-out.
Further, the specification teaches that the endothelial barrier disruption by neutrophiles was suggested to occur by the release of reactive oxygen species (ROS) (see page 5). The specification discloses the term “MPO activity” refers to at least one of MAPK and NFĸB activation, ROS production, surface integrin upregulation, and degranulation, as well as decreased apoptosis leading to enhanced inflammation in the lung (see page 45). The specification discloses by modulating and elevating the MPO levels, using the methods of the invention, the present specification further provides methods for treating conditions associated for example with ROS-deficiency and/or MPO-deficiency… the MPO-related condition that may be applicable for the methods of the invention may be associated with reduced or deficient ROS levels (see page 74).
However, the specification fails to disclose that Applicant was in possession of the large genera of methods of reducing the expression and/or activity of MPO in a mammalian subject as recited in the claims. Specifically, the specification fails to disclose that Applicant was in possession of administering an effective amount of any CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in any undifferentiated BM cell; any composition or vehicle comprising the CRISPR/Cas system; or a nucleic acid molecule encoding the CRISPR/Cas system. It is noted that the targets are not limited to MPO, but can be any molecule either upstream or downstream in the MPO protein signaling or activation. The only requirement is that the expression or activity is affected. This encompassed an extremely large genus of possible targets. Further, the specification fails to disclose administering multiple CRISPR-Cas systems.
Additionally, the specification fails to disclose that Applicant was in possession of a method of treating, ameliorating, inhibiting, or delaying the onset of any MPO-related condition or disorder in a mammalian subject. Also, the specification fails to demonstrate that Applicant was in possession of inhibiting NETosis and related conditions in any mammalian subject. Lastly, the specification fails to disclose that Applicant was in possession of the claimed method of inhibiting production of ROS.
Although the specification discloses of utilizing CRISPR-Cas9 mediated KO experiments on the BM cells of MS mice models to determine MPO levels and of AD mice models to determine peroxidase activity, MPO-mRNA and amyloid-β levels, functional behavior, inflammation activity, and APOE expression, the claims are not limited to these constructs or conditions, and are inclusive of any gRNA that targets any protospacer within the MPO gene. This indicates that there are hundreds, if not thousands, of possible compositions and disorders encompassed by the claims. Thus, the claims encompass a vast genus of CRISPR/Cas systems – MPO expression modulations that have the claimed functions. However, the specification provides limited guidance on the structure and steps required to impart the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of MPO reducing CRISPR/Cas systems because, inter alia, the specification does not disclose a correlation between the necessary structure of the CRISPR/Cas system-gRNA and the function(s) recited in the claims; and thus, the specification does not define the claimed genus and encompassed species, except by function. Further, the specification fails to provide method steps that result in treating, ameliorating, inhibiting, or delaying the onset of any MPO-related condition or disorder or inhibiting NETosis and related conditions in any mammalian subject. Although the term “protein” does impart some structure, the structure that is common to proteins is generally unrelated to its specific binding function; therefore, correlation is less likely for proteins than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecules’ function, it does not describe the substance itself. A definition of function does not suffice to describe the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of proteins, particularly in binding site sequences, even one of skill in the art cannot envision the structure of a protein by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of CRISPR/Cas systems and gRNA compositions and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of peptides has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. 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).
Applicant has not shown possession of a representative number of species of methods of reducing the expression and/or activity of Myeloperoxidase (MPO) in a mammalian subject, the method comprises the step of administering to said subject an effective amount of at least one of: (a) at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated bone marrow (BM) cell of said subject; and (b) at least one undifferentiated BM cell or undifferentiated BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO. Even more so, Applicant has not shown possession of a representative number of species of treating, ameliorating, inhibiting or delaying the onset of an MPO-related condition or disorder or NETosis related condition in a mammalian subject, the method comprises the step of administering to said subject a therapeutically effective amount of at least one of: (a) at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated BM cell of said subject; and (b) at least one undifferentiated BM cell or undifferentiated BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO, said CRISPR/cas system comprises at least one of: (i) at least one CRISPR/cas protein, or any nucleic acid molecule encoding said Cas protein; and (ii) at least one nucleic acid sequence comprising at least one gRNA that targets a protospacer within the MPO gene, or any nucleic acid sequence encoding said gRNA; or any composition or vehicle comprising at least one of (i) and (ii).
The disclosure of only one or two 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.") (MPEP 2163).
The instant claims do not fully describe the required method, or present any form of specific threshold or other standards that would allow the method to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of CRISPR/Cas systems and MPO-related conditions or disorders, claimed only be a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous proteins and gRNAs had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of CRISPR/Cas systems claimed only by a partial structure and functional characteristic(s). Thus the method described by the instant specification encompasses an overly broad genus, and there is no correlation between the steps of the method, the structure of the CRISPR/Cas systems, and the functional outcome.
As stated above, Applicant has not demonstrated possession of the overly broad genus of methods of reducing the expression and/or activity of MPO comprising administering a CRISPR/Cas system. For example, Ma et al. (ACS Appl. Mater. Interfaces 2022, 14, 6358−6369; previously submitted in Office Action mailed 05/30/2024) disclose of biomimetic, pH-responsive metal organic framework (MOF) nanoparticles to deliver carbon nanodots (C-dot) nanozyme and CRISPR/Cas9 system for site-specific treatment of ulcerative colitis (UC) (see Abstract). In this system, C-dots and CD98 CRISPR/Cas9 plasmid were successfully encapsulated into MOF carrier by a one-pot approach and then camouflaged with macrophage membrane (see Abstract). Cas9 plasmids with two different CD98-targeting gRNAs were constructed on the basis of plasmid pX458 (see pg. 6361, left column). Ma et al. disclose that MPO activity could reflect the degree of neutrophil infiltration at inflammatory sites, could be used for evaluating the severity of UC (see pg. 6366, left column). After inducing dextran sulfate sodium (DSS), MPO activity was increased while treatment with the CRISPR/Cas system decreased the MPO activity; indicating that neutrophil infiltration was decreased and the severity of UC was mitigated (see pg. 6366, left column).
Additionally, Yan et al. (Sci. Adv. 7, eabj0624 (2021); previously submitted in Office Action mailed 05/30/2024) disclose of a CRISPR-Cas9 prodrug nanosystem (termed NanoProCas9) that combines the targeted delivery and the conditional activation of CRISPR-Cas9 for the precision therapy of inflammatory bowel disease (see Abstract). NanoProCas9 is composed of (i) cationic poly(β-amino ester)(PBAE) capable of complexing plasmid DNA encoding destabilized Cas9 (dsCas9) nuclease, (ii) a layer of biomimetic cell membrane coated on PBAE/plasmid nanocomplexes for the targeted delivery of PBAE/dsCas9 complexes, and (iii) the stimuli-responsive precursory molecules anchored on the exofacial membrane (see Abstract). Similarly to the teachings of Ma et al. above, Yan et al. found that MPO activity was highly elevated in the colon of mice in the colitis group and was markedly decreased in the NanoProCas9-treated group (see pg. 8, left column; Fig. 5F).
Colamartino et al (Blood 142 (2023) 7120) developed a gene therapy approach to PAH in which autologous hematopoietic stem cells (HSCs) will undergo gene editing using CRISPR/Cas9 to achieve bi-allelic disruption of the MPO gene (see entire document). These MPO-knock-out HSCs will then be autologous transplanted; that autologous transplantation of hematopoietic stem and progenitor cells (HSPC) in which the MPO gene is disrupted is expected to prevent progression of PAH due to the essential role of neutrophil MPO activity on disease development (see 3rd paragraph). Colamartino et al identified a sgRNA that leads to high frequency disruption of MPO in primary human CD34+ HSPC, leading to efficient elimination of MPO protein in the resultant neutrophils; that sequence was assessed for genome-wide off-target and showed no detectable locus, validating it as a lead candidate for safe gene editing strategy (see 4th paragraph). Colamartino et al validated in an in vitro neutrophil differentiation model the functional efficiency of the knock-out; MPO KO differentiated cells exhibit reduced NETosis and absence of MPO protein (see 5th paragraph). An optimized gene editing protocol for HSC was optimized and showed consistent allelic disruption over 80%; the edited cells retain hematopoietic potential and showed no skewing in the generated lineages in an in vitro colony forming assay (see 5th paragraph).
Lastly, Jerke et al (Kidney International (2025) 108, 145–149) disclose of a CRISPR-Cas9 mediated proteinase 3 (PR3) autoantigen deletion as a treatment strategy for anti-neutrophil cytoplasmic autoantibody-associated vasculitis (ANCA-AAVs) (see title and entire document). Jerke et al disclose that ANCA-AAVs are life-threatening systemic autoimmune diseases wherein patients lose tolerance to either PR3 or MPO and consequently develop PR3-ANCA or MPO-ANCA (see pg. 145, right col.). Jerke et al disclose of a ribonucleoprotein (RNP) complex of Cas9 protein and a PR3-specific single guide-RNA was transfected into human CD34+ HSPC by electroporation (see Abstract). Figures 1(g) and 1(h) demonstrate that the CRISPR/Cas complex disrupted PR3 protein but did not impact the intracellular ROS producti8on and degranulation of MPO indicating that PR3 is dispensable for a variety of neutrophil defense responses and for constitutive apoptosis that is pivotal to inflammation resolution (see pg. 147, right col.). Jerke et al found that PR3 gene editing strongly reduced PR3-ANCA binding to and activation of neutrophils – a central vascular injury mechanism in AAV (see pg. 149, left col.). Jerke et al disclose that AAV is suited for a gene editing approach because the disease features autoimmunity to a single autoantigen such as PR3 and MPO (see pg. 147, left col).
As such, the art indicates there are known species of methods of reducing the expression and/or activity of MPO comprising administering a CRISPR/Cas system that is structurally different than the compounds disclosed in the instant application.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of compounds by the functions of reducing the expression and/or activity of MPO. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed CRISPR/Cas systems, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9; previously submitted in Office Action mailed 05/30/2024), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990; previously submitted in Office Action mailed 05/30/2024) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988; previously submitted in Office Action mailed 05/30/2024) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98; previously submitted in Office Action mailed 05/30/2024) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400; previously submitted in Office Action mailed 05/30/2024) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al. (Bioinformatics, 34(4), 2018, 660–668; previously submitted in Office Action mailed 05/30/2024), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937; previously submitted in Office Action mailed 05/30/2024). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed CRISPR/Cas systems could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
Regarding nucleic acid-based therapeutics, in this case gRNAs, the efficacy of any possible DNA or RNA based therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al. (Advanced Drug Delivery Reviews 59 (2007) 75–86; previously submitted in Office Action mailed 05/30/2024), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al. (Leukemia and Lymphoma (1997) Vol. 24. pp. 267-281; previously submitted in Office Action mailed 05/30/2024) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three-dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al. (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24; previously submitted in Office Action mailed 05/30/2024) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13).
Specifically, regarding CRISPR/Cas9-mediated genome editing, Peng et al. (FEBS Journal 283 (2016) 1218–1231; previously submitted in Office Action mailed 05/30/2024) disclose that the CRISPR/Cas9 system has improved tremendously with respect to exploring the pathogenesis of diseases and correcting disease mutations, as well as phenotypes, due to short gRNAs (sgRNAs) precisely directing Cas9 to target sites and functions as an endonuclease to efficiently produce breaks in DNA double stands (see Abstract). However, there are still pitfalls regarding this system. Firstly, Cas9 can recognize genomic loci under the guidance of sgRNAs that bind to 20 target sequences (see pg. 1222, left column). However, sgRNAs with +85 nucleotide tracrRNA tails demonstrated concatenated and interspaced two base mismatches, which occurred in the proximal region of PAM, which greatly reduced Cas9 activity thus suggesting that excessively truncated gRNA would also result in Cas9 losing cutting activity (see pg. 1222, left column). Further, excessive sgRNA:Cas9 complexes may give rise to off-target effects as a result of the inevitable complementarity of nonspecific sequences in the genome (see pg. 1222, right column). Secondly, rational sgRNA design is of prime concern as CRISPR/Cas9 systems are highly programmable (see pg. 1223, left column). It’s assumed that Cas9/sgRNA complexes could cleave DNA in the presence of PAM and an adjacent complementary target sequence, however, many experiments show that some sgRNAs are less efficient or even inactive (see pg. 1223, left column). Thirdly, delivery methods need to be optimized. Peng et al. disclose that the demand for large fragment expression, multiple plasmids have been used to target different sites; however, all or part of the plasmids are often randomly integrated into the host genome (see pg. 1223, right column). Additionally, delivering via transfection are inefficient in primary cells and may lead to cytotoxicity, and once transfected plasmid DNA can also persist inside the cells for several days, which may aggravate off-target effects (see pg. 1225, right column). Delivery via electroporation or microinjection may be stressful to cells and may be inefficient (see pg. 1225, right column). With the use of viral vectors to deliver CRISPR systems, IDLVs are used to transfer CRISPR systems into mammalian cells but Cas9 expression may persist after IDLV delivery in quiescent and slowly dividing cells leading to high off-target effects (see pg. 1226, left column). Lastly, some of the fundamental attributes of the CRISPR/cas9 system remain unclear, including the catalytic mechanism of Cas9, the mechanisms of underlying target sites identification and the basis for PAM-dependence (see pg. 1228, right column).
Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Additionally, given the teachings of Peng et al., the claimed CRISPR/Cas9 system cannot be predicted based on several different aspects such as gRNA design, delivery methods, and off-target effects. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as CRISPR/Cas9 gene editing systems, oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA/RNA, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different peptide amino acid sequences which would have the recited functions, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all peptides.
Lastly, Applicants have not shown possession of a representative number of species of CRISPR/Cas systems. As noted above, the claims are generic for the components of the compositions. 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.") (MPEP 2163).
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed MPO epigenome modifying compositions. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of recombinant proteins as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
Applicant respectfully traverses the written description rejection (see pages 32-37 of the Remarks filed on 09/03/2025).
Applicant has amended the claims to specify use of the CRISPR/Cas system to inhibit and/or reduce MPO expression and/or activity … The CRISPR/Cas systems are discussed in detail throughout pages 23 to 40. Specifically, general structural characteristics of the various CRISPR/Cas classes are provided on page 26, while the type II system is described in paragraphs 2-4 of page 27… the CRISPR/Cas systems relevant to the present claims are not only described in technical and functional detail, but also possess well-defined common structural elements, namely, a Cas nuclease and a guide RNA sequence, along with a common functional mechanism of site-specific cleavage of a target sequence directed by the guide RNA (see pages 32-35 of the Remarks)… Applicant has amended the claims to limit the term “MPO-related disorders” to specific conditions described in detail in the specification. More specifically, the claims are now limited to AD, MS, PAH, ANCA-AAV, and ANCA-AAGN (see pages 36-37 of the Remarks).
Response to Arguments
Applicant's arguments filed 09/03/2025 have been fully considered but they are not persuasive.
Examiner acknowledges the amendments to the claims to specify use of the CRISPR/Cas system to inhibit and/or reduce MPO expression and/or activity, and limiting the term “MPO-related disorders” to specific conditions. However, the specification as well as the claims indicates that the CRISPR/Cas system may be provided as nucleic acid molecules, specifically in a delivery vector or vehicle (see pg. 26). The specification also disclose that RNA guided DNA binding protein nuclease may be a CRISPR Class 2 system (see pg. 27). Additionally, the specification discloses that the CRISPR type II system as used herein requires the inclusion of two essential components: a gRNA and a non-specific CRISPR-associated endonuclease (Cas9) (see pg. 27). Therefore, the usage of “CRISPR/Cas system” in the claims does not overcome the lack of structure-function correlation. While Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require specific functionality for the CRISPR/Cas system, but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the agents/components. For example, the CRISPR/Cas system is defined by its ability to reduce the expression and/or activity of MPO in a mammalian subject. In both the base claims and the dependent claims, for at least one agent/component in each claim, the claims only describe what the agent/component does, not what the agents/components are. Even when given possible sequences from which to select a fragment of a peptide that would reduce MPO, NETosis, and ROS production, the question remains about which one(s) of the encompassed systems would actually perform the claimed function. While methods to identify the systems with the required function may be routine in the art, the fact that any experimentation is required to figure out exactly what is encompassed necessarily means that applicant has not sufficiently described the claimed subject matter.
There are thousands of possible CRISPR/Cas system-gRNAs encompassed by the instant claims. One of skill in the art could not immediately envisage the encompassed species in each genus from the guidance provided in the instant specification and claims. Applicant has supplied a limited number of species of CRISPR/Cas system-gRNAs. The claims are not limited to these species. The claims encompass all CRISPR/Cas systems that reduce MPO, NETosis, and ROS production. This encompasses an extremely broad genus of systems with a specific function, for which no correlating structure is provided. While one of skill in the art could likely screen for said CRISPR/Cas systems and gRNAs, the mere fact that experimentation is necessary to identify the members of the genus indicates that proper description has not been provided.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene' s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The protein/nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Further, arguments relating to the isolation of an antibody with specific characteristics may be more appropriately directed to the invention' s enablement, since the method of isolating would detail how to make the invention. However, the enablement of the invention has not been rejected by the Examiner.
As such, the written description rejection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Shelley & Van der Veen et al
Claims 1, 6, 8-11, 13, 18, 44, and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Shelley (WO 2017/048872 A1; publication date: 03/23/2017) and further in view of Van der Veen et al (Antioxid. Redox Signal. 11 (2009), 2899–2937).
Shelley discloses of method of treating a hematopoietic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that targets a hematopoietic disorder-associated molecule (see claim 14; pg. 51, 1st and 2nd paras.). Shelley discloses that the agent is a genomic DNA editing methodology, such as a CRISPR-Cas system, wherein the genomic DNA editing results in inhibition of the target molecules (see pg. 46, 3rd para.; pg. 50, 2nd para.). Claims 16 and 17 of Shelley disclose that the hematopoietic disorder-associated molecule resides inside of hematopoietic cell or secreted thereof, wherein said hematopoietic cell is undifferentiated bone marrow cell of the types set forth on page 9 (1st para.). Shelley discloses that MPO is a hematopoietic disorder-associated molecule that is targeted by their invention (see pgs. 23 and 44).
Shelley fails to disclose of treating a subject affected by or suffering from AD, MS, PAH, ANCA-AAV, and ANCA-AAGN as recited in instant claims 1 and 10.
However, Van der Veen et al disclose of the molecular mechanisms of action and relevance of MPO to human health and disease (see entire document). Van der Veen et al disclose that MPO is a heme-containing peroxidase abundantly expressed in neutrophils and to a lesser extent in monocytes (see Abstract). For a long time, MPO has been considered to be a bactericidal enzyme whose main function is to generate reactive oxygen species (ROS) that contribute to the destruction and killing of engulfed pathogens; however, recent evidence has extended this view by demonstrating that MPO is also intimately involved in cellular homeostasis and is an important factor in the initiation and progression of various inflammatory diseases (see pg. 2900, left col.). Van der Veen et al disclose that inhibition of ROS production reduces proliferative and fibrotic changes and improves renal function in experimental diabetic nephropathy (see pg. 2916, right col.). Van der Veen et al also suggest that MPO is able to activate neutrophils directly and control neutrophil adhesion to endothelial cells through binding to CD11b/CD18 which could explain the observed reduction in migrated neutrophils (see pg. 2916, right col). Van der Veen et al provide extensive evidences about the involvement of MPO in AD, MS, and ANCA-related disorders (see pg. 2902, right col.; pgs. 2914-2923). For example, Van der Veen et al disclose that MPO-ANCA-activated neutrophils produce ROS that cause oxidative stress (see pg. 2920, left col.).
As such, it would have been obvious to one of skill in the art to combine the teachings of Shelley and Van der Veen et al to develop the claimed invention. One would have been motivated to do so as Shelley discloses of reducing the expression of a hematopoietic disorder-associated molecule (i.e., MPO) comprising administering a genomic DNA editing methodology, such as a CRISPR-Cas system, wherein the genomic DNA editing results in inhibition of the target molecules (see pg. 46, 3rd para.; pg. 50, 2nd para.). While Shelley does not recite of subjects having the conditions or disorders recited in the instant claims, one would have a reasonable expectation that the method recited in Shelley would also be beneficial in treating the conditions of the present invention based on the teachings of Van der Veen et al. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Thus, it is prima facie obvious to develop the present invention based on the combined teachings of Shelley and Van der Veen et al because one would understand that administering a CRISPR/Cas system to reduce MPO expression and/or activity in undifferentiated bone marrow cells would also result in inhibition of NETosis and ROS.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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17/142,072
Claims 1, 5-6, 8-11, 13, 16, 18, 44 and 46-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8-9, 11-13, 20, and 22-27 of copending Application No. 17/142,072.
The ‘072 application is drawn to a method of reducing the expression and/or activity of Myeloperoxidase (MPO) in a mammalian subject, the method comprising the step of administering to said subject an effective amount of at least one of: (a) at least one clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR associated (cas) protein system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated bone marrow (BM) cell of said subject, said CRISPER/Cas system comprising at least one of: (i) at least one CRISPR/cas protein; and at least one guide RNA (gRNA) that targets a protospacer within the MPO gene, (ii) a nucleic acid molecule encoding said Cas protein, or a nucleic acid construct comprising said nucleic acid sequence; and a nucleic acid sequence encoding said gRNA or a nucleic acid construct comprising said nucleic acid sequence; and (iii) composition comprising (i) or (ii); and (b) at least one undifferentiated BM cell, or BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO, said undifferentiated BM cell being a hematopoietic stem cell (HSC) or a hematopoietic progenitor cell; wherein said subject is a subject affected by or suffering from at least one MPO-related condition or disorder selected from the group consisting of: Alzheimer's disease (AD), multiple sclerosis (MS), Pulmonary arterial hypertension (PAH), Antineutrophil cytoplasmic autoantibody (ANCA)-Associated Vasculitis (AVV) and ANCA-associated glomerulonephritis (AAGN) (see claim 1).
Claim 3 is drawn to the method according to claim 1, wherein: (i) said at least one gRNA targets a protospacer comprised within at least one exon of the MPO gene encoding at least one MPO protein domain present in the MPO protein; or (ii) said at least one gRNA targets a protospacer comprised within at least one exon of the MPO gene encoding at least one MPO protein domain present in the MPO protein and wherein said MPO protein domain is at least one of MPO pro- peptide, MPO signal peptide, MPO light chain subunit and MPO heavy chain subunit wherein said MPO pro-peptide domain is encoded by exon 2, exon 3, and exon 4 of the MPO gene.
Claim 4 is drawn to the method according to claim 3, wherein said at least one gRNA targets at least one protospacer comprised within at least one of: exon 1, exon 2, exon 3, exon 5, exon 6, exon 8, exon 9 and exon 12 of the human MPO gene.
Claim 5 is drawn to the method according to claim 4, wherein said gRNA comprises the nucleic acid sequence as denoted by any one of: SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 50, SEQ ID NO: 55, SEQ ID NO: 60, SEQ ID NO: 63, SEQ ID NO: 66, SEQ ID NO: 71, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 115, SEQ ID NO: 118, SEQ IDNO:122-SEQ ID NO: 125, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 139, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 145, or any combinations of said gRNAs.
Claim 6 is drawn to the method according to claim 1, wherein said at least one undifferentiated BM cell or BM cell population of (b) is: (i) at least one BM cell or cell population modified by and/or comprising at least CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in said cells, wherein said at least one undifferentiated BM cell or BM cell population is of an autologous or of an allogenic source; or (ii) said at least one undifferentiated BM cell or cell population is a BM cell or BM cell population of an allogeneic subject exhibiting an inhibited or eliminated expression and/or activity of MPO.
Claim 8 is drawn to the method according to claim 1, for treating, ameliorating, inhibiting or delaying the onset of an MPO-related condition or disorder in a mammalian subject, the method comprising the step of administering to said subject a therapeutically effective amount of at least one of: (a) at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated BM cell of said subject, said CRISPR/Cas system comprising at least one of: (i) at least one CRISPR/cas protein; and at least one gRNA that targets a protospacer within the MPO gene; (ii) a nucleic acid molecule encoding said Cas protein, or a nucleic acid construct comprising said nucleic acid sequence; and a nucleic acid sequence encoding said gRNA or a nucleic acid construct comprising said nucleic acid sequence; and (iii) composition comprising (i) or (ii); and (b) at least one undifferentiated BM cell or BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO; wherein said MPO-related condition or disorder is selected from the group consisting of: AD, MS, PAH, AVV and AAGN.
Claim 9 is drawn to the method according to claim 8, wherein said at least one undifferentiated BM cell or BM cell population is: (a) at least one BM cell or BM cell population modified by, and/or comprising at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in said cells, wherein said undifferentiated BM cell or BM cell population is of an autologous or of an allogenic source; or (b) said at least one undifferentiated BM cell or BM cell population is a BM cell or cell population of an allogeneic subject exhibiting an inhibited or eliminated expression and/or activity of MPO.
Claim 11 is drawn to the method according to claim 8, wherein: (a) said at least one gRNA targets a protospacer comprised within at least one exon of the MPO gene encoding at least one MPO protein domain present in the MPO protein; or (b) said at least one gRNA targets a protospacer comprised within at least one exon of the MPO gene encoding at least one MPO protein domain present in the MPO protein, wherein said MPO protein domain is at least one MPO pro-peptide, MPO signal peptide, MPO light chain subunit and MPO heavy chain subunit: wherein said MPO pro-peptide domain is encoded by exon 2, exon 3, and exon 4 of the MPO gene.
Claim 12 is drawn to the method according to claim 11, wherein said at least one gRNA targets at least one protospacer comprised within at least one of exon 1, exon 2, exon 3, exon 5, exon 6, exon 8, exon 9 and exon 12 of the human MPO gene.
Claim 13 is drawn to the method according to claim 12, wherein said gRNA comprises the nucleic acid sequence as denoted by any one of: SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 50, SEQ ID NO: 55, SEQ ID NO: 60, SEQ ID NO: 63, SEQ ID NO: 66, SEQ ID NO: 71, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 115, SEQ ID NO: 118, SEQ ID NO: 122, SEQ ID NO: 125, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 139, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 145, or any combinations of said gRNAs.
Claim 20 is drawn to a method for inhibiting neutrophil extracellular trap (NET) activation and release, and/or NETosis in a mammalian subject, said method comprising the step of administering to said subject a therapeutically effective amount of at least one of: (a) at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated BM cell of said subject, the Cas system comprising at least one of: (i) at least one CRISPR/cas protein; and at least one gRNA that targets a protospacer within the MPO gene; (ii) a nucleic acid molecule encoding said Cas protein, or a nucleic acid construct comprising said nucleic acid sequence; and nucleic acid sequence encoding said gRNA or a nucleic acid construct comprising said nucleic acid sequence; and (b) undifferentiated BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO; (c) any composition comprising at least one of the CRISPR/Cas system of (a), and/or the undifferentiated BM cell population of (b).
Claim 22 is drawn to a method for treating, ameliorating, inhibiting or delaying the onset of an MPO-related condition or disorder in a mammalian subject, the method comprising the step of administering to said subject a therapeutically effective amount of at least one of: (a) at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated BM cell of said subject, said CRISPR/Cas system comprising at least one of:(i) at least one CRISPR/cas protein; and at least one gRNA that targets a protospacer within the MPO gene; said at least one gRNA targets a protospacer comprised within at least one exon of the MPO gene encoding at least one MPO protein domain present in the MPO protein;(ii) a nucleic acid molecule encoding said Cas protein, or a nucleic acid construct comprising said nucleic acid sequence; and a nucleic acid sequence encoding said gRNA or a nucleic acid construct comprising said nucleic acid sequence; and(iii) a composition comprising (i) or (ii); and(b) at least one undifferentiated BM cell or BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO; wherein said MPO-related condition or disorder is selected from the group consisting of: AD, MS, PAH, AVV and AAGN.
Claim 23 is drawn to the method according to claim 22, wherein said at least one gRNA targets a protospacer comprised within at least one exon of the MPO gene encoding at least one MPO protein domain present in the MPO protein and wherein said MPO protein domain is at least one of MPO pro-peptide, MPO signal peptide, MPO light chain subunit and MPO heavy chain subunit; wherein said MPO pro-peptide domain is encoded by exon 2, exon 3, and exon 4 of the MPO gene.
Claim 24 is drawn to the method according to claim 23, wherein said at least one gRNA targets at least one protospacer comprised within at least one of: exon 1, exon 2, exon 3, exon 5, exon 6, exon 8, exon 9 and exon 12 of the human MPO gene.
Claim 25 is drawn to the method according to claim 24, wherein said gRNA comprises the nucleic acid sequence as denoted by any one of: SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 50, SEQ ID NO: 55, SEQ ID NO: 60, SEQ ID NO: 63, SEQ ID NO: 66, SEQ ID NO: 71, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 115, SEQ ID NO: 118, SEQ ID NG:122, SEQ ID NO: 125, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO:139, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 145, or any combinations of said gRNAs.
Claim 26 is drawn to the method according to claim 22, wherein said at least one undifferentiated BM cell or BM cell population of (b) is at least one BM cell or BM cell population modified by and/or comprising at least one CRISPR/Cas system that inhibits or reduces the expression and/or activity of MPO in said cells, wherein said at least one undifferentiated BM cell or BM cell population is of an autologous or of an allogenic source.
Claim 27 is drawn to the method according to claim 22, wherein said at least one undifferentiated BM cell or BM cell population of (b) is a BM cell or BM cell population of an allogeneic subject exhibiting an inhibited or eliminated expression and/or activity of MPO.
The instant claims are drawn to a method of reducing the expression and/or activity of Myeloperoxidase (MPO) in a mammalian subject, the method comprising the step of administering to said subject an effective amount of at least one of: (a) at least one clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR associated (cas) protein system that inhibits or reduces the expression and/or activity of MPO in at least one undifferentiated bone marrow (BM) cell of said subject, said CRISPR/Cas system comprising at least one of: clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR associated (cas) protein system; and (b) at least one undifferentiated BM cell or undifferentiated BM cell population exhibiting a reduced or inhibited expression and/or activity of MPO; wherein said subject is a subject affected by or suffering from at least one MPO-related condition or disorder selected from the group consisting of: Alzheimer's disease (AD), multiple sclerosis (MS), Pulmonary arterial hypertension (PAH), Antineutrophil cytoplasmic autoantibody (ANCA)-Associated Vasculitis (AVV) and ANCA-associated glomerulonephritis (AAGN).
Specifically, the claims are drawn to gRNA comprises the nucleic acid sequence as denoted by any one of: SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 50, SEQ ID NO: 55, SEQ ID NO: 60, SEQ ID NO: 63, SEQ ID NO: 66, SEQ ID NO: 71, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 88 and SEQ ID NO: 91 (see claims 5, 16, and 46).
As such, the ‘072 claims anticipate the instant claims.
The instant application and the ‘072 application have overlapping scopes, but are not identical. The ‘072 application claims are broader in scope, providing for a method that comprises compositions or vehicles that comprise a gene editing compound, while the instant application only recites the gene editing compound in the method. Further, ‘072 application is drawn to a wider scope of gRNA sequences comprising SEQ ID NO: 118, SEQ ID NO: 125, SEQ ID NO: 115, SEQ ID NO: 122, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 137, SEQ ID NO: 139, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 145, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 50, SEQ ID NO: 55, SEQ ID NO: 60, SEQ ID NO: 63, SEQ ID NO: 66, SEQ ID NO: 71, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 88 and SEQ ID NO: 91, or any combinations of said gRNAs (see claims 5, 13, and 16). Instant SEQ ID NOs: 33, 34, 35, 42, 47, 50, 55, 60, 63, 66, 71, 74, 77, 80, 85, 88, and 91 share 100% identity to SEQ ID NOs: 33, 34, 35, 42, 47, 50, 55, 60, 63, 66, 71, 74, 77, 80, 85, 88, and 91 of the reference application, but does not recite all of the sequences listed in the ‘072 application claims.
This is a provisional nonstatutory double patenting rejection.
Applicant’s Argument
In order to obviate this rejection, a terminal disclaimer is being filed on even date herewith. Accordingly, this rejection has now been obviated. Reconsideration and withdrawal thereof are therefore respectfully urged. (See pages 49 and 50 of the Remarks filed on 09/03/2025).
Response to Arguments
Applicant's arguments filed 09/03/2025 have been fully considered but they are not persuasive. At the time of examining the amendments and remarks filed on 09/03/2025, a terminal disclaimer has yet to be filed. As such, the provisional double patenting rejection is maintained.
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Conclusion
No claims are allowed.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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