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 .
Applicant’s response of 10/20/2025, including amendments to the specification, has been received and entered into the application file.
Claims 1, 2, 8-10, 12, 14, and 17-19 were amended in the claim set filed 10/20/2025.
Claims 3, 4, 7, 13, 15, and 21 were cancelled in the claim set filed 10/20/2025.
Accordingly, claims 1, 2, 5, 6, 8-12, 14, and 16-20 are pending and under consideration.
Status of Prior Objections/Rejections
RE: Specification
The specification was previously objected to for using a trade name or mark used in commerce without properly identifying it as such. The amendments to the specification filed 10/20/2025 have obviated the basis of the prior objection.
The rejection of record is hereby withdrawn.
RE: Claim Objections
Claims 2, 12-15, 18, and 19 were previously objected to for a number of informalities.
The cancellation of claims 13 and 15 renders the objections thereof moot.
The amendments to claims 1, 12, 14, 18, and 19 have obviated the basis of the prior objection.
The objections of record are hereby withdrawn.
RE: Claim Rejections - 35 USC § 112
►Claims 1-17 were previously 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 treating Duchenne muscular dystrophy (DMD) by administering to a subject in need thereof a composition comprising a CRISPR activation (CRISPRa) system that upregulates the cortical isoform of dystrophin, does not reasonably provide enablement for treating any disease or disorder associated with aberrant dystrophin by administering a composition that upregulates any brain isoform of dystrophin.
The cancellation of claims 3, 4, 7, 13, and 15 renders the rejections thereof moot.
The amendments to instant claim 1 have obviated some of the basis of the prior rejection. Amended claim 1 is drawn to therapeutic upregulation of a brain isoform of dystrophin, reciting targeting the promoters of both the cortical and Purinkje isoforms of dystrophin. Although the working examples of the instant specification disclose only therapeutic upregulation of the cortical isoform of dystrophin, the disclosure of Bastianutto et al., 2001 is considered to teach one of ordinary skill in the art that the Purkinje isoform of dystrophin would predictably have therapeutic effects in treating patients with mutations that specifically affect the muscle isoform of dystrophin (abstract; page 2633, column 2, paragraph 1; see Claim Rejections - 35 USC § 103 for detailed analysis). However, the language of amended instant claim 1 does not clearly limit the upregulated brain isoform of dystrophin to Purkinje and cortical isoforms. While amended instant claim 1 recites that the CRISPRa system targets the promoter regions of cortical or Purkinje dystrophin, the claim explicitly recites upregulation of “a brain isoform of dystrophin” (bolded emphasis added), without explicitly reciting that the upregulated brain isoform is the Purkinje or cortical isoform.
Accordingly, the rejection of record is hereby maintained, as set forth in detail below.
RE: Claim Rejections - 35 USC § 103
►Claims 1-7 were previously rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019 in view of Bastianutto et al., 2002, as evidenced by Barrangou and Doudna, 2016.
►Claims 8-11 were previously rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019, Bastianutto et al., 2002, and Barrangou and Doudna, 2016 as applied to claim 7, and further in view of Ramos et al., 2019.
►Claims 12 and 13 were previously rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019, Bastianutto et al., 2002, and Barrangou and Doudna, 2016, as applied to claim 7, and further in view of Doorenweerd et al., 2017, Hugnot et al., 1993, and Martella et al., 2019.
►Claims 14 and 15 were previously rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019, Bastianutto et al., 2002, and Barrangou and Doudna, 2016, as applied to claim 7, and further in view of Doorenweerd et al., 2017, Bastianutto et al., 2001, and Martella et al., 2019.
►Claim 17 was previously rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019, Bastianutto et al., 2002, Barrangou and Doudna, 2016, and Ramos et al., 2019 as applied to claim 7, and further in view of Kemaladewi et al., 2019.
►Claim 18 was previously rejected under 35 U.S.C. 103 as being unpatentable over Salva et al., 2007 in view of Bastianutto et al., 2002, Doorenweerd et al., 2017, Martella et al., 2019, and WO 2018/128689 (hereinafter Baxalta).
►Claim 19 was previously rejected under 35 U.S.C. 103 as being unpatentable over Ramos et al., 2019 in view of Bastianutto et al., 2002, Doorenweerd et al., 2017, Martella et al., 2019, and WO 2018/128689 (hereinafter Baxalta).
►Claim 21 was previously rejected under 35 U.S.C. 103 as being unpatentable over Ramos et al., 2019, Bastianutto et al., 2002, Doorenweerd et al., 2017, Martella et al., 2019, and WO 2018/128689 (hereinafter Baxalta) as applied to claim 19, and further in view of Hugnot et al., 1993 and Bastianutto et al., 2001.
The cancellation of claims 3, 4, 7, 13, 15, and 21 renders the rejections thereof moot.
Applicant has traversed the rejections of record regarding claims 1, 2, 5, and 6, asserting that the applied references, either alone or in combination, fail to render the features of amended claim 1 obvious. Applicant has traversed the rejections of record regarding the remainder of the instant claim set, asserting that the claims are not rendered obvious over the cited art, as the applied references, either alone or in combination, fail to render the features of amended claim 1 (from which the other claims directly or indirectly depend) obvious.
Applicant further asserts that the cited art fails to meet the standards for an obviousness rejection, as none of the cited art discloses or motivates combining the applied references in an attempt to arrive at the features of claim 1 with a reasonable expectation of success.
In response, while Applicant’s argument has been fully considered, it is not found persuasive. As previously set forth, CRISPR activation (CRISPRa) is a rapidly-evolving technology that is known to have in vivo therapeutic applications (reviewed in Matharu et al., 2019). While the cited art, when considered alone, does not disclose the treatment method of amended instant claim 1, the Examiner maintains that the cited art does disclose the treatment method of amended instant claim 1, when considered in combination from the view of someone of ordinary skill in the art. As previously set forth, Min et al., 2019 discloses that CRISPR-mediated upregulation of therapeutic proteins (such as utrophin) is capable of rescuing the mutant phenotype associated with DMD mutations. Additionally, both Bastianutto et al., 2001 and Bastianutto et al., 2002 disclose therapeutic implications of upregulation/activation of expression of the dystrophin B isoform (expressed primarily in cortical and cerebellar tissues (Bastianutto et al., 2001: abstract; page 2628, column 1, paragraph 2)) and CP isoform (expressed in cerebellar Purkinje cells (Bastianutto et al., 2001: abstract; page 2627, column 2, paragraph 2)) in skeletal muscle cells in patients affected by mutations impacting the muscle isoform of dystrophin (Bastianutto et al., 2001: page 2633, column 2, paragraph 1; Bastianutto et al., 2002: page 619, column 1, paragraph 2), as in DMD (instant specification: page 12, lines 8-11). Thus, Min et al., 2019, in combination with Bastianutto et al., 2001 and Bastianutto et al., 2002 is considered to motivate one of ordinary skill in the art to apply the CRISPR-mediated upregulation of therapeutic proteins disclosed in Min et al., 2019 to upregulation of cortical and Purkinje dystrophin isoforms, as disclosed in Bastianutto et al., 2001 and Bastianutto et al., 2002 (albeit by different methodology).
As Applicant has noted, CRISPRa is a system with variable efficacy (see Figure 3 of Martella et al., 2019; cited by Applicant). However, while the cited Figure of Martella et al., 2019 does disclose this variable efficacy, every gene depicted therein was ultimately successfully upregulated by one of the 6 CRISPRa systems depicted in the same Figure. It is thus considered that it is within the realm of routine experimentation for one of ordinary skill in the art to optimize CRISPRa systems for the intended application, as such optimization experimentation is routinely performed, as shown in Martella et al., 2019. Thus, it is considered that Min et al., 2019, in combination with Bastianutto et al., 2001 and Bastianutto et al., 2002 is motivates one of ordinary skill in the art to apply the CRISPR-mediated upregulation of therapeutic proteins disclosed in Min et al., 2019 to the therapeutic upregulation of cortical and Purkinje dystrophin isoforms disclosed in Bastianutto et al., 2001 and Bastianutto et al., 2002 (albeit by different methodology). Based on the disclosure of Martella et al., 2019, it would have been within the realm of routine experimentation for one of ordinary skill in the art to optimize CRISPRa systems for the intended application.
Accordingly, while the rejection of record is withdrawn, amendments to the instant claim set have necessitated new grounds of rejection, set forth in detail below.
New/Maintained Grounds of Objection/Rejection
Claim Objections
Claims 12 and 14 are objected to because of the following informalities:
Amended claims 12 and 14 respectively recite that “the target region of the gRNA comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 4-7” or “SEQ ID NO: 8-10” (bolded emphasis added). In both claims, while multiple sequences are recited, the preceding “SEQ ID NO” is reflective of a single recited sequence rather than multiple sequences. Accordingly, it would be remedial to amend the instant claim language such that it comports with standard grammatical and/or linguistic conventions, for example by reciting “SEQ ID NOs: 4-7” or “SEQ ID NOs: 8-10” (bolded emphasis added).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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, 5, 6, 8-12, 14, 16, and 17 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 treating Duchenne muscular dystrophy (DMD) by administering to a subject in need thereof a composition comprising a CRISPR activation (CRISPRa) system that upregulates the cortical or Purkinje isoform of dystrophin, does not reasonably provide enablement for treating DMD by administering a composition that upregulates any brain isoform of dystrophin. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 1, 5, 6, 8-12, 14, 16, and 17 are drawn to a method of treating DMD in a subject in need thereof, the method comprising administering to the subject a composition that upregulates a brain isoform of dystrophin, limited to Purkinje and cortical dystrophin isoforms at dependent claim 2, which is not included in this rejection. Dependent claims 5, 6, 8-12, 14, 16, and 17 further limit the nature of the treated disease or disorder, as well as the systems and vectors administered to the subject to upregulate brain isoforms of dystrophin. However, these limitations do not overcome the breadth of the claimed invention, as further addressed below. The nature of the invention is complex in that one must be able to treat DMD by upregulating any brain isoform of dystrophin. Moreover, the instant claim language encompasses upregulation of any brain isoform of dystrophin while reciting CRISPRa guides that target only the cortical and Purkinje dystrophin promoter regions.
Breadth of the claims: The claims broadly encompass treating DMD by administering a composition to upregulate any brain isoform of dystrophin. Per in re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991 ), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. As elaborated below, the specification teaches administration of AAV-packaged CRISPRa to upregulate the cortical isoform of dystrophin to treat DMD in hDMD-D2 mice. This narrow disclosure does not enable the broad scope of protection sought in the claims in that the cortical isoform of dystrophin is only one brain isoform of dystrophin. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: While the specification envisions treatment of a disease or disorder associated with aberrant or absent dystrophin via administering a composition to upregulate a brain isoform of dystrophin, it only teaches administration of an AAV-packaged CRISPRa system to upregulate the cortical isoform of dystrophin (using guide C7 (SEQ ID NO: 6)) in muscle tissue (using the CK8e promoter) in hDMD-D2 mice, as well as in vitro administration of an AAV-packaged CRISPRa system to upregulate the cortical isoform of dystrophin (using guides C7 and CS (SEQ ID NOs: 6 and 7) and the CK8e promoter) (examples 1-3; pages 23-25;figures3, 4, and 7). However, the instant specification is silent as to both the treatment efficacy of upregulating any other brain isoforms of dystrophin and its applicability to treating DMD.
Predictability and state of the art: It is known in the field that the DMD gene produces several isoforms with unique canonical expression patterns. These isoforms comprise Dp427m (i.e. the muscular isoform), Dp427p (i.e. the Purkinje isoform), Dp427c (i.e. the cortical isoform), and Dp71, which is the most abundant dystrophin in the brain and liver and the predominant isoform in astrocyte and glioma cell cultures (Leiden, 2006; of record). Therefore, Dp71 appears to meet the limitation of "a brain isoform of dystrophin," as instantly claimed. However, Cox et al., 1994 (of record) discloses that Dp71 has a much different structure than many other dystrophin isoforms, being only 71 kDa rather than 427 kDa, as are isoforms Dp427m, Dp427p, and Dp427c, listed above (page 333, column 1, paragraph 1). Cox et al., 1994 (of record) discloses generation of transgenic mdx mice that ectopically express Dp71 in skeletal and cardiac muscle (page 336, column 1, paragraph 2), and while Dp71 expression in skeletal muscle restores dystrophin-associated proteins on the sarcolemma membrane, it was unable to prevent the dystrophic pathology of the transgenic mdx mice (page 336, column 2, paragraph 2). These results emphasize that not all brain isoforms of dystrophin will predictably have therapeutic benefit in treating DMD, as at least one brain isoform (Dp71) is known to be ineffective in treating DMD.
Amount of experimentation necessary: The quantity of experimentation needed to carry out the full scope of the claimed method is large. One could not solely rely upon the guidance provided in the instant disclosure or prior art. One would be required to test the effects of upregulating each known brain isoform of dystrophin in DMD for the ability to treat DMD in a subject in need thereof. The success of treating DMD via upregulation of one isoform would not necessarily provide a reasonable expectation of success with upregulating a different isoform in treating DMD. Accordingly, a large amount of inventive effort would be required to carry out the claimed invention of treating DMD by administering a composition that upregulates any brain isoform of dystrophin.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1, 5, 6, 8-12, 14, 16, and 17 are not considered to be fully enabled by the instant disclosure.
Claim Rejections - 35 USC § 103
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.
Claims 1, 2, 5, 6, 12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019 (of record) in view of Bastianutto et al., 2002 (of record), Bastianutto et al., 2001 (of record), Matharu et al., 2019, Doorenweerd et al., 2017 (of record), and Hugnot et al., 1993 (of record), as evidenced by Barrangou and Doudna, 2016 (of record).
With regard to amended instant claim 1, which recites “a method of treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is associated with aberrant or absent dystrophin, the method comprising administering to the subject a composition that upregulates a brain isoform of dystrophin, wherein the disease is Duchenne Muscular Dystrophy (DMD), wherein the composition comprises a CRISPR activation (CRISPRa) system that upregulates the brain isoform of dystrophin, wherein the CRISPRa system comprises a guide RNA (gRNA) that targets the cortical dystrophin promoter or the Purkinje dystrophin promoter region, and wherein a target region of the gRNA comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 4-10,” as previously set forth, Min et al., 2019 discloses that CRISPR technology has been successfully used in mice to correct DMD mutations (i.e. mice with a disease or disorder associated with aberrant or absent dystrophin, as instantly claimed) and restore dystrophin function (page 245, paragraph 4). This technology has been applied to delete out-of-frame exons and restore the correct open reading frame, to skip mutant exons to generate a shortened but semifunctional dystrophin protein, to reframe exons, to knock-in missing or mutated exons, to correct point mutations with base editing, as well as to upregulate expression of a therapeutic protein capable of rescuing the mutant phenotype (pages 245-248; figure 2). While Min et al., 2019 only discloses this expression upregulation for purposes of producing utrophin (page 248, paragraph 2), other proteins are also thought to be therapeutic. As previously set forth, the Examiner notes that using CRISPR to upregulate expression of a targeted gene is a technique known in the field as CRISPR activation (CRISPRa), as taught in Barrangou and Doudna, 2016 (figure 5). Thus, although Min et al., 2019 does not explicitly disclose CRISPRa-mediated upregulation of therapeutic expression by name, their disclosure nonetheless reads on the instantly claimed CRISPRa system, as evidenced by Barrangou and Doudna, 2016. Additionally, Min et al., 2019 discloses that this CRISPR machinery may be delivered via viral vectors such as lentivirus, adenovirus, and adeno-associated virus (AAV) (page 248, paragraph 4).
As previously set forth, Bastianutto et al., 2002 discloses that a subgroup of patients with DMD gene mutations have been diagnosed with X-linked dilated cardiomyopathy (XLDC), in which these patients are diagnosed with mono- or biventricular dilated cardiomyopathy in the absence of skeletal muscle weakness (page 614, column 1, paragraph 1 -page 614, column 2, paragraph 1). Intriguingly, a further subgroup of XLDC patients present with mutations that eliminate muscle (M) dystrophin, which should result in severe skeletal muscle weakness but instead only affects the cardiac muscles (page 614, column 2, paragraph 2). It is thought that the severe skeletal muscle weakness canonically associated with these DMD mutations is prevented by increased expression of the brain (B) and cerebellar Purkinje (CP) dystrophin isoforms in the skeletal muscle but not in the heart (page 614, column 2, paragraph 2). Thus, the disclosure of Bastianutto et al., 2002 establishes that brain isoforms of dystrophin, when expressed in the skeletal muscle, are sufficient to rescue the canonical skeletal muscle weakness phenotype associated with DMD mutations that do not produce appropriate dystrophin. Additionally, Bastianutto et al., 2001 discloses that upregulation/activation of the dystrophin B isoform (expressed primarily in cortical and cerebellar tissues-considered to read on the instantly claimed cortical isoform (abstract; page 2628, column 1, paragraph 2)) and CP isoform (expressed in cerebellar Purkinje cells-considered to read on the instantly claimed Purkinje isoform (abstract; page 2627, column 2, paragraph 2)) has therapeutic potential in skeletal muscle cells in patients affected by mutations impacting the muscle isoform of dystrophin (page 2633, column 2, paragraph 1). This is further supported by the disclosure of Bastianutto et al., 2002 (see page 619, column 1, paragraph 2).
It is thus considered that the cited art collectively discloses that upregulation/activation of expression of the cortical and Purkinje isoforms of dystrophin (i.e. by CRISPR methodology) in skeletal muscle cells in DMD patients would predictably treat DMD by providing a functional dystrophin isoform capable of rescuing the mutant phenotype of skeletal muscle cells lacking the functional muscle isoform of dystrophin. However, none of the above-cited art discloses that the upregulation is accomplished specifically by a CRISPRa system comprising a gRNA targeting the cortical dystrophin promoter or the Purkinje dystrophin promoter region (i.e. SEQ ID NOs: 4-10). These deficiencies are cured by the various secondary sources set forth below.
Matharu et al., 2019 discloses that CRISPRa upregulation is accomplished in vivo by targeting a CRISPR enzyme (such as dCas9) fused to a transcriptional activator (such as VP64) to the promoter region of the targeted gene by a user-specified gRNA (abstract; page 2, column 1, paragraph 1; Figure 1), thereby promoting expression of the targeted gene. The Examiner notes that this system reads on the transcriptional activation disclosed at Figure 2 of Min et al., 2019, although Min et al., 2019 does not explicitly disclose that such transcriptional activation is accomplished via CRISPRa (as set forth above and further taught in Barrangou and Doudna, 2016). Matharu et al., 2019 further discloses the utility of the CRISPRa system for in vivo treatment of diseases such as obesity (page 2, column 1, paragraph 2-titled Up-regulation of Sim1 in vivo by transgenic CRISPRa rescues obesity). Accordingly, it is considered that Matharu et al., 2019 motivates in vivo therapeutic applications of CRISPRa, such as those depicted in Figure 2 of Min et al., 2019.
Regarding the specifically claimed gRNA target regions, as set forth above, Matharu et al., 2019 discloses that CRISPRa functions by targeting the promoter region of the chosen gene with a gRNA that recruits a CRISPR enzyme (such as dCas9) fused to a transcriptional activator (such as VP64) to said promoter region (abstract; page 2, column 1, paragraph 1; Figure 1). As previously set forth, Doorenweerd et al., 2017 discloses that the promoter regions of each known human dystrophin isoform (including cortical dystrophin isoform Dp427c) derived from the DMD gene have been identified (indicated with red boxes in Figure 1). Per the disclosure of Doorenweerd et al., 2017, dystrophin isoform Dp427c is the cortical isoform, predominantly expressed in neurons of the cortex and the CA regions of the hippocampus (page 2, paragraph 2). Additionally, Hugnot et al., 1993 discloses remarkable conservation of the brain-specific sequence of the dystrophin gene (Figure 1), stating that even sequences upstream and downstream of the exons (such as promoters) are highly conserved, which is unusual in the field (page 395, column 2, paragraph 2). The sequence disclosed in Hugnot et al., 1993 (figure
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1) comprises SEQ ID NO 7, as in instant claim 1 (alignment shown below).
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Furthermore, per the disclosure of Doorenweerd et al., 2017, dystrophin isoform Dp427p has two reported variants expressed in cerebellar Purkinje cells (page 2, paragraph 2). Additionally, Bastianutto et al., 2001 discloses that the CP dystrophin isoform promoter (i.e. the Purkinje isoform or Dp427p) corresponds to GenBank accession no. AF324931 (figure 2), which comprises SEQ ID NO 9, as in instant claim 1 (alignment shown below).
While the cited art is silent as to the ability of these sequences to be targeted by CRISPRa, Matharu et al., 2019 discloses that CRISPRa is known to have therapeutic in vivo applications by targeting user-specified promoters, while Min et al., 2019 discloses that upregulation of therapeutic proteins by methodology that reads on CRISPRa is known to specifically have therapeutic applications in the treatment of DMD.
With regard to claim 2, which recites “the brain isoform of dystrophin [upregulated by the method of claim 1] is selected from the group consisting of Purkinje and cortical,” as set forth above, the disclosure of Bastianutto et al., 2002 establishes that brain isoforms of dystrophin, when expressed in the skeletal muscle, are sufficient to rescue the canonical skeletal muscle weakness phenotype associated with DMD mutations that do not produce appropriate dystrophin. Additionally, Bastianutto et al., 2001 discloses that upregulation/activation of the dystrophin B isoform (expressed primarily in cortical and cerebellar tissues-considered to read on the instantly claimed cortical isoform (abstract; page 2628, column 1, paragraph 2)) and CP isoform (expressed in cerebellar Purkinje cells-considered to read on the instantly claimed Purkinje isoform (abstract; page 2627, column 2, paragraph 2)) has therapeutic potential in skeletal muscle cells in patients affected by mutations impacting the muscle isoform of dystrophin (page 2633, column 2, paragraph 1).
With regard to claim 5, which recites “the subject [treated by the method of claim 1] has an absence of muscle dystrophin,” Min et al., 2019 discloses that a lack of muscle dystrophin in DMD patients renders the sarcolemma fragile, impairs intracellular signaling, results in myocyte necrosis and inflammatory infiltration, and ultimately leads to replacement of muscle with fibrotic and fatty tissue (page 240, paragraph 5).
With regard to claim 6, which recites “the subject [treated by the method of claim 1] has a mutation or deletion in the promoter and/or exon 1 of the muscle dystrophin gene,” Bastianutto et al., 2002 discloses analysis of deletion breakpoints in two DMD-XLDC patients lacking the promoter and first exon of the muscle dystrophin gene (page 615, column 1, paragraph 2). As noted above, DMD-XLDC patients are spared the severe skeletal muscle pathology associated with the absence of muscle dystrophin due to elevated expression of nonmuscle dystrophin isoforms (i.e. brain and cerebellar Purkinje isoforms) (page 618, column 1, paragraph 2).
With regard to amended claim 12, which recites “the target region of the gRNA [of claim 1] comprises a nucleotide sequence selected from the group consisting of SEQ ID NO[s]: 4-7, and wherein the CRISPRa system targets dystrophin in the cortical dystrophin promoter region,” as set forth above, Doorenweerd et al., 2017 discloses that the promoter regions of each known human dystrophin isoform (including cortical dystrophin isoform Dp427c) derived from the DMD gene have been identified (indicated with red boxes in Figure 1). Per the disclosure of Doorenweerd et al., 2017, dystrophin isoform Dp427c is the cortical isoform, predominantly expressed in neurons of the cortex and the CA regions of the hippocampus (page 2, paragraph 2). Additionally, Hugnot et al., 1993 discloses remarkable conservation of the brain-specific sequence of the dystrophin gene (Figure 1), stating that even sequences upstream and downstream of the exons (such as promoters) are highly conserved, which is unusual in the field (page 395, column 2, paragraph 2). The sequence disclosed in Hugnot et al., 1993 (figure
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1) comprises SEQ ID NO 7, as in instant claim 12 (alignment shown below).
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With regard to amended claim 14, which recites “the target region of the gRNA [of claim 1] comprises a nucleotide sequence selected from the group consisting of SEQ ID NO[s]: 8-10, and wherein the CRISPRa system targets dystrophin in the Purkinje dystrophin promoter region,” as set forth above, per the disclosure of Doorenweerd et al., 2017, dystrophin isoform Dp427p has two reported variants expressed in cerebellar Purkinje cells (page 2, paragraph 2). Additionally, Bastianutto et al., 2001 discloses that the CP dystrophin isoform promoter (i.e. the Purkinje isoform or Dp427p) corresponds to GenBank accession no. AF324931 (figure 2), which comprises SEQ ID NO 9, as in instant claim 14 (alignment shown below).
Therefore, given that Min et al., 2019 discloses that upregulation of therapeutic proteins by methodology that reads on CRISPRa (per Matharu et al., 2019) has therapeutic applications in the treatment of DMD; that Bastianutto et al., 2002 and Bastianutto et al., 2001 disclose that upregulation/activation of expression of the cortical and Purkinje isoforms of dystrophin in the skeletal muscle cells of DMD patients (including DMD-XLDC patients) provides a functional dystrophin isoform capable of rescuing the mutant phenotype of skeletal muscle cells lacking the functional muscle isoform of dystrophin; that Matharu et al., 2019 motivates in vivo therapeutic applications of CRISPRa in which gRNAs target the promoter of a user-specified gene; and that Doorenweerd et al., 2017, Hugnot et al., 1993, and Batianutto et al., 2001 collectively disclose the promoter sequences of the cortical and Purkinje isoforms of dystrophin (which comprise SEQ ID NOs: 7 and 9, respectively), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to target the promoter region of the cortical and Purkinje isoforms of dystrophin with a gRNA compatible with the CRISPRa system to predictably upregulate/activate expression of the cortical and Purkinje isoforms of dystrophin via the CRISPRa system, thereby treating DMD by rescuing the mutant phenotype of skeletal muscle cells lacking the functional muscle isoform of dystrophin. One would have been motivated to make such a modification in order to receive the expected benefit of treating DMD by rescuing the mutant phenotype of skeletal muscle cells lacking the functional muscle isoform of dystrophin.
Claims 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019 (of record) in view of Bastianutto et al., 2002 (of record), Bastianutto et al., 2001 (of record), Matharu et al., 2019, Doorenweerd et al., 2017 (of record), and Hugnot et al., 1993 (of record), as evidenced by Barrangou and Doudna, 2016 (of record), as applied to claim 1 above, and further in view of Ramos et al., 2019 (of record).
The combined disclosures of Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 are described above and applied as before. However, these disclosures do not teach the AAV vector comprising a tissue-specific promoter of instant claim 8.
With regard to amended claim 8, which recites “the CRISPRa system [of the method of claim 1] comprises an AAV vector comprising a tissue-specific promoter,” instant claims 9 and 11 further limit the tissue-specific promoter of instant claim 8 to be “a muscle-specific promoter” or “a muscle creatine kinase 8 (CK8e) promoter”, respectively. Ramos et al., 2019 discloses treatment for DMD via delivery of novel micro-dystrophins using AAV vectors in which expression of the micro-dystrophins was regulated by the strong and compact muscle-restricted CK8e regulatory cassette (abstract), which reads on the instantly claimed tissue-specific promoter, muscle-specific promoter, and CK8e promoter of instant claims 8, 9, and 11.
With regard to claim 10, which recites “the promoter [of the method of claim 8] yields expression of the vector in skeletal muscle tissue and/or cardiac tissue,” Ramos et al., 2019 discloses that the CK8e regulatory cassette displays strong skeletal and cardiac muscle-restricted expression (page 624, column 2, paragraph 2).
However, while Ramos et al., 2019 discloses delivering therapeutic micro-dystrophins to treat DMD via skeletal and cardiac muscle expression-restricted AAV vectors, they do not disclose packaging a CRISPRa system into an AAV vector. As set forth above, Min et al., 2019 discloses various gene editing/manipulation strategies using CRISPR machinery (i.e. CRISPRa, as evidenced by Matharu et al., 2019) to treat disorders such as DMD (pages 245-248; figure 2). Additionally, Min et al., 2019 discloses that CRISPR machinery has been successfully delivered via viral vectors such as lentivirus, adenovirus, and adeno-associated virus (AAV) (page 248, paragraph 4).
Given that Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 collectively disclose the CRISPRa-based treatment of DMD recited at instant claim 1; that Ramos et al., 2019 discloses that the CK8e regulatory cassette strongly restricts expression of AAV cargo to skeletal and cardiac muscle; and that Min et al., 2019 discloses that CRISPR machinery is known to be successfully delivered via viral vectors such as AAV, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to package the therapeutic CRISPRa machinery of claim 1 into the CK8e-driven skeletal and cardiac muscle expression-restricted therapeutic AAV of Ramos et al., 2019 to predictably express the therapeutic dystrophin isoforms set forth above in skeletal and cardiac muscle. One would have been motivated to make such a modification in order to receive the expected benefit of expressing therapeutic dystrophin isoforms in skeletal and cardiac muscle.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019 (of record) in view of Bastianutto et al., 2002 (of record), Bastianutto et al., 2001 (of record), Matharu et al., 2019, Doorenweerd et al., 2017 (of record), and Hugnot et al., 1993 (of record), as evidenced by Barrangou and Doudna, 2016 (of record), as applied to claim 1 above, and further in view of Kemaladewi et al., 2019 (of record).
The combined disclosures of Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 are described above and applied as before. However, these disclosures do not teach the single vector CRISPRa system of instant claim 17.
With regard to claim 17, which recites “the CRISPR activation (CRISPRa) system [of the method of claim 1] is a single vector system,” while Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 collectively disclose the CRISPRa system of claim 1, they do not teach delivering the CRISPRa system via a single vector system. However, this deficiency is cured by, Kemaladewi et al., 2019 which discloses upregulating expression of Lama1 in mice modeling muscular dystrophy (specifically congenital muscular dystrophy type 1A) by using an AAV9 vector carrying CRISPRa machinery, including gRNAs targeting the Lama1 promoter (abstract). These vector constructs are depicted in figure 2. Notably, one of their tested vectors comprised a single gRNA, facilitating delivery of the AAV9 vector carrying CRISPRa machinery in a single vector, as instantly claimed.
Given that Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 collectively disclose the CRISPRa-based treatment of DMD recited at instant claim 1, and that Kemaladewi et al., 2019 discloses the efficacy of treating congenital muscular dystrophy type 1A with a single vector system (i.e. AAV9-CRISPRa vector targeting the Lama1 promoter), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to package the AAV-CRISPRa vector targeting therapeutic dystrophin isoforms for upregulation into a single vector system as disclosed in Kemaladewi et al., 2019 to predictably upregulate therapeutic dystrophin isoform expression. One would have been motivated to make such a modification in order to receive the expected benefit of simplifying the CRISPRa vector while maintaining its efficacy in upregulating the targeted gene of interest (i.e. the Purkinje isoform of the dystrophin gene).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019 (of record) in view of Bastianutto et al., 2002 (of record), Bastianutto et al., 2001 (of record), Matharu et al., 2019, Doorenweerd et al., 2017 (of record), Hugnot et al., 1993 (of record), Salva et al., 2007 (of record), and WO 2018/128689 (hereinafter Baxalta; of record), as evidenced by Barrangou and Doudna, 2016 (of record).
With regard to claim 18, which recites “a pharmaceutical composition comprising an AAV vector comprising an MHCK7 promoter and a guide RNA (gRNA) sequence that targets the cortical dystrophin promoter region or the Purkinje dystrophin promoter region, wherein a target region of the gRNA sequence comprises a nucleotide sequence selected from the group consistin of SEQ ID NOs: 4-10,” as set forth above regarding amended instant claim 1, Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 collectively disclose the CRISPRa-based treatment of DMD recited at instant claim 1, wherein DMD is treated by CRISPRa-mediated upregulation of the cortical or Purkinje forms of dystrophin.
As set forth in greater detail above, Matharu et al., 2019 specifically discloses that CRISPRa upregulation is accomplished in vivo by targeting a CRISPR enzyme (such as dCas9) fused to a transcriptional activator (such as VP64) to the promoter region of the targeted gene by a user-specified gRNA (abstract; page 2, column 1, paragraph 1; Figure 1), thereby promoting expression of the targeted gene. CRISPR-mediated upregulation of therapeutic proteins is indicated to be applicable to the treatment of DMD (Min et al., 2019: Figure 2). Additionally, Bastianutto et al., 2002 and Bastianutto et al., 2001 teach that increased expression of brain isoforms of dystrophin (such as the Purkinje and cortical isoforms) in skeletal muscle of patients lacking functional dystrophin expression prevents the severe skeletal muscle weakness canonically associated with DMD mutations that interfere with functional dystrophin expression (Bastianutto et al., 2002: page 614, column 2, paragraph 2; Bastianutto et al., 2001: page 2633, column 2, paragraph 1). However, Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 are silent as to the instantly claimed AAV vector comprising an MHCK7 promoter.
This deficiency is cured by Salva et al., 2007, which discloses that the MHCK7 cassette is a hybrid promoter consisting of short regulatory regions from skeletal and cardiac muscle-specific genes that is highly active in both skeletal and cardiac muscle (page 327, column 1, paragraph 3). They further disclose that using the MHCK7 cassette in an AAV delivery vector (delivered systemically) is ideal for Duchenne muscular dystrophy gene therapy and for expressing other potentially therapeutic cDNAs in striated muscles (page 327, column 1, paragraph 3). However, while Salva et al., 2007 discloses an AAV vector comprising an MHCK7 promoter, they do not disclose its incorporation into a pharmaceutical composition, nor do they disclose it further comprising a gRNA sequence targeting the cortical of Purkinje dystrophin promoter regions.
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Regarding the specifically claimed gRNA target regions, as set forth above, Matharu et al., 2019 discloses that CRISPRa functions by targeting the promoter region of the chosen gene with a gRNA that recruits a CRISPR enzyme (such as dCas9) fused to a transcriptional activator (such as VP64) to said promoter region (abstract; page 2, column 1, paragraph 1; Figure 1). As previously set forth, Doorenweerd et al., 2017 discloses that the promoter regions of each known human dystrophin isoform (including cortical dystrophin isoform Dp427c) derived from the DMD gene have been identified (indicated with red boxes in Figure 1). Per the disclosure of Doorenweerd et al., 2017, dystrophin isoform Dp427c is the cortical isoform, predominantly expressed in neurons of the cortex and the CA regions of the hippocampus (page 2, paragraph 2). Additionally, Hugnot et al., 1993 discloses remarkable conservation of the brain-specific sequence of the dystrophin gene (Figure 1), stating that even sequences upstream and downstream of the exons (such as promoters) are highly conserved, which is unusual in the field (page 395, column 2, paragraph 2). The sequence disclosed in Hugnot et al., 1993 (figure 1) comprises SEQ ID NO 7, as in instant claim 1 (alignment shown below).
Furthermore, per the disclosure of Doorenweerd et al., 2017, dystrophin isoform Dp427p has two reported variants expressed in cerebellar Purkinje cells (page 2, paragraph 2). Additionally, Bastianutto et al., 2001 discloses that the CP dystrophin isoform promoter (i.e. the Purkinje isoform or Dp427p) corresponds to GenBank accession no. AF324931 (figure 2), which
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comprises SEQ ID NO 9, as in instant claim 1 (alignment shown below).
With regard to the limitation that the AAV vector of instant claim 18 is incorporated into a pharmaceutical composition, Baxalta discloses pharmaceutical compositions comprising AAV vectors (abstract).
Given that Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 collectively disclose the CRISPRa-based treatment of DMD recited at instant claim 1, wherein CRISPR gRNAs target transcriptional activation machinery to the promoter regions of the cortical or Purkinje dystrophin isoforms (said target regions comprising SEQ ID NOs: 7 and 9), thereby upregulating expression of the cortical or Purkinje dystrophin isoforms; and that Salva et al., 2007 discloses robust and specific expression of gene therapy machinery in cardiac and skeletal muscles driven by the MHCK7 promoter in an AAV delivery vector (which may be packaged into a pharmaceutical composition as disclosed in Baxalta), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to package the AAV vector comprising an MHCK7 promoter and a gRNA sequence targeting the cortical or Purkinje dystrophin promoter region into a pharmaceutical composition to predictably upregulate cortical or Purkinje dystrophin isoform expression in skeletal and cardiac muscle. One would have been motivated to make such a modification in order to receive the expected benefit of strongly and specifically expressing Purkinje dystrophin isoforms in skeletal and cardiac muscle, thereby rescuing the severe skeletal muscle weakness canonically associated with DMD mutations that interfere with functional dystrophin expression.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Min et al., 2019 (of record) in view of Bastianutto et al., 2002 (of record), Bastianutto et al., 2001 (of record), Matharu et al., 2019, Doorenweerd et al., 2017 (of record), Hugnot et al., 1993 (of record), Ramos et al., 2019 (of record), and WO 2018/128689 (hereinafter Baxalta; of record), as evidenced by Barrangou and Doudna, 2016 (of record).
With regard to claim 19, which recites “a pharmaceutical composition comprising an AAV vector comprising a CK8e promoter and a gRNA sequence that targets the cortical dystrophin promoter region or the purkinje [sic] dystrophin promoter region,” as set forth above regarding amended instant claim 1, Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 collectively disclose the CRISPRa-based treatment of DMD recited at instant claim 1, wherein DMD is treated by CRISPRa-mediated upregulation of the cortical or Purkinje forms of dystrophin.
As set forth in greater detail above, Matharu et al., 2019 specifically discloses that CRISPRa upregulation is accomplished in vivo by targeting a CRISPR enzyme (such as dCas9) fused to a transcriptional activator (such as VP64) to the promoter region of the targeted gene by a user-specified gRNA (abstract; page 2, column 1, paragraph 1; Figure 1), thereby promoting expression of the targeted gene. CRISPR-mediated upregulation of therapeutic proteins is indicated to be applicable to the treatment of DMD (Min et al., 2019: Figure 2). Additionally, Bastianutto et al., 2002 and Bastianutto et al., 2001 teach that increased expression of brain isoforms of dystrophin (such as the Purkinje and cortical isoforms) in skeletal muscle of patients lacking functional dystrophin expression prevents the severe skeletal muscle weakness canonically associated with DMD mutations that interfere with functional dystrophin expression (Bastianutto et al., 2002: page 614, column 2, paragraph 2; Bastianutto et al., 2001: page 2633, column 2, paragraph 1). However, Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 are silent as to the instantly claimed AAV vector comprising a CK8e promoter.
This deficiency is cured by Ramos et al., 2019, which discloses treatment for DMD via delivery of novel micro-dystrophins using AAV vectors in which expression of the micro-dystrophins was regulated by the strong and compact muscle-restricted CK8e regulatory cassette (abstract; as set forth above).
However, while Ramos et al., 2019 discloses an AAV vector comprising a CK8e promoter, they do not disclose its incorporation into a pharmaceutical composition, nor do they disclose it further comprising a gRNA sequence targeting the cortical of Purkinje dystrophin promoter regions.
Regarding the specifically claimed gRNA target regions, as set forth above, Matharu et al., 2019 discloses that CRISPRa functions by targeting the promoter region of the chosen gene with a gRNA that recruits a CRISPR enzyme (such as dCas9) fused to a transcriptional activator (such as VP64) to said promoter region (abstract; page 2, column 1, paragraph 1; Figure 1). As previously set forth, Doorenweerd et al., 2017 discloses that the promoter regions of each known human dystrophin isoform (including cortical dystrophin isoform Dp427c) derived from the DMD gene have been identified (indicated with red boxes in Figure 1). Per the disclosure of Doorenweerd et al., 2017, dystrophin isoform Dp427c is the cortical isoform, predominantly expressed in neurons of the cortex and the CA regions of the hippocampus (page 2, paragraph 2). Additionally, Hugnot et al., 1993 discloses remarkable conservation of the brain-specific sequence of the dystrophin gene (Figure 1), stating that even sequences upstream and downstream of the exons (such as promoters) are highly conserved, which is unusual in the field (page 395, column 2, paragraph 2). The sequence disclosed in Hugnot et al., 1993 (figure 1) comprises SEQ ID NO 7, as in instant claim 1 (alignment shown below).
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Furthermore, per the disclosure of Doorenweerd et al., 2017, dystrophin isoform Dp427p has two reported variants expressed in cerebellar Purkinje cells (page 2, paragraph 2). Additionally, Bastianutto et al., 2001 discloses that the CP dystrophin isoform promoter (i.e. the Purkinje isoform or Dp427p) corresponds to GenBank accession no. AF324931 (figure 2), which comprises SEQ ID NO 9, as in instant claim 1 (alignment shown below).
With regard to the limitation that the AAV vector of instant claim 18 is incorporated into a pharmaceutical composition, Baxalta discloses pharmaceutical compositions comprising AAV vectors (abstract).
Given that Min et al., 2019, Bastianutto et al., 2002, Bastianutto et al., 2001, Matharu et al., 2019, Doorenweerd et al., 2017, Hugnot et al., 1993, and Barrangou and Doudna, 2016 collectively disclose the CRISPRa-based treatment of DMD recited at instant claim 1, wherein CRISPR gRNAs target transcriptional activation machinery to the promoter regions of the cortical or Purkinje dystrophin isoforms (said target regions comprising SEQ ID NOs: 7 and 9), thereby upregulating expression of the cortical or Purkinje dystrophin isoforms; and that Ramos et al., 2019 discloses robust and specific expression of therapeutic micro-dystrophins in muscles driven by the CK8e promoter in an AAV delivery vector (which may be packaged into a pharmaceutical composition as disclosed in Baxalta), it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to package the AAV vector comprising a CK8e promoter and a gRNA sequence targeting the Purkinje dystrophin promoter region into a pharmaceutical composition to predictably upregulate Purkinje dystrophin isoform expression in muscle. One would have been motivated to make such a modification in order to receive the expected benefit of strongly and specifically expressing Purkinje dystrophin isoforms in muscle, thereby rescuing the severe skeletal muscle weakness canonically associated with DMD mutations that interfere with functional dystrophin expression.
Allowable Subject Matter
Claim 20 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
An updated sequence search of the patent and non-patent literature did not return any sequences published prior to the effective filing date of the instant invention that comprise the sequence of SEQ ID NO: 11. Accordingly, SEQ ID NO: 11 is deemed to be free of the prior art. However, claim 20 depends from claim 19, which stands rejected under 35 U.S.C. § 103.
Conclusion
Claims 1, 2, 5, 6, 8-12, 14, and 16-19 are rejected.
Claims 12, 14, and 20 are objected to.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL, Ph.D./ Primary Examiner, Art Unit 1637