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 .
Claims 1-20, of record 12/21/22 are pending. Prosecution on the merits commences for claims 1-20.
PRIORITY
The instant application, filed 12/21/22 is a CIP of 16/088,570, filed 09/26/2018 (now abandoned), which is a 371 of PCT/US17/25315, filed 03/31/2017, which claims priority to US Provisional Application No. 62/433,985, filed 12/14/2016; US Provisional Application No. 62/433,987, filed 12/14/2016; and US Provisional Application No. 62/315,988, filed 03/31/2016. Thus, the earliest possible priority for the instant application is 3/31/2016.
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CLAIMS
Claim Interpretation
Claim 1 requires the modified AAV vector comprises, a recombinant AAV-based genome “consisting essentially of” an AAV backbone, a control element, and a transgene “consisting essentially of” CNTFRα.”
The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in original) (Prior art hydraulic fluid required a dispersant which appellants argued was excluded from claims limited to a functional fluid "consisting essentially of" certain components. In finding the claims did not exclude the prior art dispersant, the court noted that appellants’ specification indicated the claimed composition can contain any well-known additive such as a dispersant, and there was no evidence that the presence of a dispersant would materially affect the basic and novel characteristic of the claimed invention. The prior art composition had the same basic and novel characteristic (increased oxidation resistance) as well as additional enhanced detergent and dispersant characteristics.). "A ‘consisting essentially of’ claim occupies a middle ground between closed claims that are written in a ‘consisting of’ format and fully open claims that are drafted in a ‘comprising’ format." PPG Industries v. Guardian Industries, 156 F.3d 1351, 1354, 48 USPQ2d 1351, 1353-54 (Fed. Cir. 1998). See also Atlas Powder v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 224 USPQ 409 (Fed. Cir. 1984); In re Janakirama-Rao, 317 F.2d 951, 137 USPQ 893 (CCPA 1963); Water Technologies Corp. vs. Calco, Ltd., 850 F.2d 660, 7 USPQ2d 1097 (Fed. Cir. 1988). For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising.” MPEP 2111.03, emphasis added.
A review of the specification finds that there is no definition of “consisting essentially of” and the phrase is only recited once in the body of the specification, at paragraph [0019] of the published specification. The remaining recitations are in claims 1 and 2 in the claims of 12/21/22, the day of filing. As such, the phrase “consisting essentially of” is interpreted as “comprising” (MPEP 2111.03).
Claim 1 requires “wherein the modified AAV vector is engineered to direct enhanced skeletal muscle expression of CNTFRα.”
The specification does not define the phrases “engineered to direct” or “enhanced skeletal muscle expression of CNTFRα.” The specification teaches that the transgene encoding CNTFRα can be encoded on any of AAV genomes 1-13, and the vectors can be administered systemically or locally (paragraphs [0049] and [0058], respectively, of the published specification). The broadest reasonable interpretation of an AAV vector “engineered to direct enhanced skeletal muscle expression of CNTFRα” comprises a recombinant AAV vector that encodes a CNTFRα transgene and expresses CNTFRα in skeletal muscle tissue.
Claim Objections
Claim 19 is objected to because of the following informalities: Claim 19 states “the AAV vector is packaged in a capsid” which should be amended to recite “the AAV genome is packaged in a capsid” or “the AAV vector comprises a capsid.” The specification utilizes “AAV vector” as the assembled virion, wherein the vector genome is packaged inside the capsid proteins.
Claim Rejections - 35 USC § 112(b) - indefinite
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 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 requires wherein the modified AAV vector is engineered to direct “enhanced” skeletal muscle expression of CNTFRα. The term “enhanced” in claim 1 is a relative term which renders the claim indefinite. The term “enhanced” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear whether “enhanced” skeletal muscle expression of CNTFRα: a) is any amount of AAV vector-derived CNTFRα skeletal muscle expression – regardless of the concomitant expression in non-skeletal muscle cells- (thus, skeletal muscle CNTFRα protein levels are “enhanced” compared to endogenous skeletal muscle CNTFRα protein levels); b) is a minimum amount of AAV vector-derived CNTFRα skeletal muscle expression (wherein only after a certain amount of skeletal muscle CNTFRα protein is expressed qualifies as “enhanced” skeletal muscle expression); c) is muscle-specific expression of AAV vector-derived CNTFRα (thus the muscle-specific AAV vector-derived CNTFRα expression is “enhanced” in comparison to all other tissues); or d) reflects a modified property of the recombinant AAV vector capsid to transduce skeletal muscle cells, compared to an unmodified recombinant AAV vector capsid (thus, a modified AAV1 capsid (AAV1.1) with increased transduction of skeletal muscle cells compared to an unmodified AAV1 capsid, has “enhanced” skeletal muscle expression).
For the purposes of prosecution, the term “enhanced” in the phrase “wherein the modified AAV vector is engineered to direct “enhanced” skeletal muscle expression of CNTFRα” is interpreted as wherein the AAV vector expresses any amount of CNTFRα in skeletal muscle, regardless of the concomitant expression in non-skeletal muscle cells.
Claim 2 recites an additional AAV vector is engineered to direct “enhanced” skeletal muscle expression of CLC and/or CLF, and is rejected for the same reasons as stated above for claim 1.
Claim 17 requires wherein the slowing disease progression comprises at least ”temporarily partially reversing paralysis”. The terms “temporarily” and “partially” in claim 17 are relative terms which renders the claim indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 3-16, and 18-20 are included in the rejection because they depend from a rejected claim.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 5-6, 8-15 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2003/0161814 to Wang, further in view of US 5,426,177 to Davis and Lee, 2013, of record, cited on Applicant’s IDS dated 12/21/22. With regard to claim 1, Wang discloses methods of treating amyotrophic lateral sclerosis (ALS) in a human subject with ALS, comprising administering an AAV vector encoding the neurotrophic factor GDNF to the subject, wherein the AAV vector expresses GDNF in skeletal muscle, and wherein the expression of GDNF results in a therapeutic effect treating ALS (Abstract, paragraphs [0012]-[0021]). Thus, the modified AAV vector is engineered to direct enhanced skeletal muscle expression of GDNF.
Wang discloses the rAAV vector genomes are modified to remove helper genes, resulting in an AAV viral genome comprising two ITRs flanking a promoter operably linked to the transgene GDNF cDNA insert (paragraphs [0058]-[0063], [0068] , [0086], [0094]-[0106], [0136]). Thus, the recombinant AAV consists essentially of an AAV backbone, a control element, and a transgene.
Wang exemplifies administering, via injection, an AAV vector encoding GDNF and expression of the recombinant GDNF protein in skeletal muscle cells of an ALS SOD1G93A (ALS) mouse model (Example 4). Expression of GDNF in the skeletal muscle in the ALS mice provided the in vivo source of GDNF protein for injured motor neurons, at least via retrograde transport (Example 4). The skeletal muscle-expressed GDNF in the motor neurons of the ALS mice resulted in greater numbers of, and larger sizes of, motor neurons, and the treated ALS mice had prolonged strength and increased survival compared to untreated ALS mice (paragraphs [0177]-[0190], FIGs 6A-E). Thus, the skeletal muscle-expressed neurotrophic factor GDNF increased the survival of motor neurons, inhibited motor neuron degeneration and slowed disease progression in treated ALS mice compared to untreated ALS controls (Example 4, paragraph [0011]).
Wang discloses the method can comprise administering more than one therapeutic transgene, on the same or different vectors (paragraph [0126]). Wang discloses ALS is a late-onset disease, exhibited in adults (paragraphs [0055], [0087]).
Wang discloses the need to continue to develop new therapeutic strategies to treat ALS, such as using AAV encoding the neurotrophic factor GDNF, stems in part because clinical trials comprising administering neurotrophic factors including GDNF, BDNF, IGF-1 and CNTF as recombinant peptides, were stopped due to lack of efficacy or severe side effects ([0005]). Wang further discloses expressing therapeutic genes in muscle cells provides a useful source of recombinant proteins in vivo because skeletal muscle is highly transducible, easily accessible and display low turnover (paragraph [0011]).
Thus, Wang establishes a gene therapy methodology for treating ALS wherein a therapeutic neurotrophic protein with neuromuscular protectivity and regenerating function is encoded within a recombinant AAV vector, administering the vector to the subject with ALS, wherein the AAV vector infects and expresses the therapeutic neurotrophic protein within the skeletal muscle of the ALS subject, wherein the skeletal muscle-expressed therapeutic neurotrophic protein is the endogenous source of therapeutic neurotrophic protein at injured motor neurons, and wherein the skeletal muscle-expressed neurotrophic therapeutic protein located within the injured motor neurons inhibits motor neuron degeneration in the ALS subject.
However, Wang does not disclose wherein the therapeutic neurotrophic transgene expressed by the AAV vector is CNTFRα, as required by instant claim 1.
Davis discloses early work on the identification and cloning of the Ciliary Neurotrophic Factor Receptor α subunit (CNTFRα), the cell surface receptor for the neurotrophic factor CNTF which has neuromuscular regenerative and protective properties, useful for treating ALS (Abstract, column 6, lines 33-42). Davis shows CNTFRα expression in both neuronal tissue and muscle tissue (column 7, lines 35-46; column 33, lines 25-44; FIG 5). Davis discloses nucleic acids encoding recombinant cell surface CNTFRα, as well as a soluble CNTFRα peptide, and methods of using them (column 33, lines 25-44; column 15, line 25- column 16, line 16; column 34, 13-62).
Because CNTFRα is the cell surface receptor for neurotrophic factor CNTF, Davis reasons that at least some CNTF function in vivo must occur within cells with CNTFRα surface expression (column 33, lines 25-44), whereas soluble CNTFRα peptide may allow for CNTF, or other peptide ligands, to function on distal cells (column 17, lines 21-26; column 34, lines 58-62).
Davis discloses recombinant CNTFRα peptides expressed on a cell surface or soluble, can be used to direct, focus or augment the physiological response to ligands which bind CNTFRα, including at least neurotrophic factor CNTF (column 14, lines 13-38; column 18, lines 18-46; column 20, line 64 – column 21, line 6; column 21, lines 1-34). Davis discloses neurotrophic factor CNTF expression and activity has been shown in many fetal and adult muscle and neuronal tissues (column 2, line 16 – column 4, line 64), and has neuromuscular regenerative and protective properties, shown to inhibit motor neuron degeneration, which is useful for treating ALS (column 3, lines 50-54; column 4, lines 38-60; column 17, lines 44-49; column 19, lines 27-44; column 33, lines 30-44).
Thus, Davis discloses the recombinant CNTFRα are used in methods of treating CNTF-related neurological or muscular disorders, wherein expression of recombinant CNTFRα directs, focuses or augments the physiological response CNTF (i.e. its neuromuscular regenerative and protective properties), wherein the CNTF can be endogenous, or supplied recombinantly (abstract, column 5, lines 50-55; column 6, lines 15-41; column 19, lines 3-56; column 27, line 4 – column 28, line 12).
Davis discloses methods of treating a neurologic disorder, including amyotrophic lateral sclerosis, or a muscular disorder, including muscular dystrophies, comprising administering to a patient in need thereof, an effective amount of CNTRFα protein or via gene therapy (column 27, line 4 – column 28, line 12; column 36, lines 10-20). Davis explicitly discloses methods of treating motor neuron degenerative diseases, including ALS, comprising administering recombinant viral vectors comprising a gene encoding CNTRFα to the patient, and expressing the CNTRFα in appropriate cells (column 27, line 3- column 28, line 5; column 36, lines 10-17). Davis discloses the recombinant virus comprises a viral backbone, a control element, and a CNTRFα cDNA insert (column 10, lines 25-50; column 12, lines 54-65; column 13, line 22- column 14, line 7; column 14, lines 44-57). Davis discloses control elements, such as promoters, include a CMV promoter, a neuron-specific promoter, or a muscle-specific promoter (column 13, line 21- column 14, line 7; column 20, lines 51-63). Davis further discloses the CNTRFα protein or viral vectors can be administered systemically or locally (column 27, lines 17-24, 43-45).
Davis does not reduce the disclosed compositions or methods to practice. As noted above, Davis discloses early work on CNTFRα, and the methods of using CNTFRα peptides are prophetic. However, Davis recognizes the dependency of CNTF and at least some of its in vivo endogenous and therapeutic function on CNTFRα expression, and explicitly articulates gene therapy methods of treating neurological conditions, including ALS, by administering recombinant viruses to the patient, wherein the virus encodes recombinant CNTFRα, infects and expresses CNTFRα in a tissue-specific manner, and wherein motor neuron degeneration is inhibited. In addition, Davis recognizes the disclosure was not complete, and thus specific embodiments therein were not limiting, and acknowledges that modifications may be made as knowledge of the relationship between CNTF, CNTFRα and neuromuscular physiology and pathophysiology advances/evolves, at least through in vitro and in vivo models (column 6, lines 33-41; column 17, line 30 – column 22, line 25; column 25, lines 25-63; column 33, lines 30-45; column 36, lines 10-20).
Lee 2013 investigates the specific role endogenous CNTFRα plays in CNTF signaling, because CNTFRα is expressed in both muscles and motor neurons, and endogenous muscle-specific CNTFRα is upregulated in response to neuronal injury and neuromuscular disease. Lee generates a conditional skeletal muscle-specific CNTRFα knock out (KO) mouse in order to elucidate the role skeletal muscle-specific CNTRFα plays in neuromuscular protection and regeneration. Following neuromuscular injury, the muscle-specific CNTFRα KO mice did not influence skeletal muscle repair, but did inhibit neuronal repair. Thus, Lee concludes endogenous muscle-expressed CNTFRα has neuroregeneration properties (Abstract, pages 13-14). Lee states “The data clearly indicate that muscle CNTFRα is required for normal axonal regeneration, in that without it the regeneration is decreased/abnormal” (page 13) and “[T]he present data reveal an essential in vivo role for muscle CNTFRα in the normal recovery of motor function following peripheral nerve lesion.” 13-14.
In addition, Lee suggests muscle-expressed CNTFRα as a potential therapeutic target in ALS treatment:
Work with genetic models of ALS indicates that exogenous CNTF administration can protect MN axons from this genetic insult. Several lines of evidence suggest that loss of MN axons is a critical event leading to ALS symptoms. However, clinical trials of systemic CNTF stopped due to unacceptable side effects, indicating any therapeutic manipulation of CNTF signaling will need to be more specifically targeted. Therefore, the present data indicating that endogenous muscle CNTFRα-dependent signaling contributes to MN axon regeneration following a different insult (nerve lesion) raises the possibility that muscle CNTFRα should be considered as a potential target in the treatment of ALS, whether this involves interventions designed to increase muscle CNTFRα expression or other approaches. Pages 15-16, internal citations deleted.
Thus, it would have been obvious to combine the method of treating ALS comprising administering an AAV vector encoding a therapeutic transgene that is skeletal muscle expressed, wherein the skeletal muscle-expressed therapeutic protein is the endogenous source of therapeutic protein at injured motor neurons, and wherein the skeletal muscle-expressed therapeutic protein located within the injured motor neurons inhibits motor neuron degeneration in the ALS subject of Wang, further with the disclosures of Davis and Lee. A skilled artisan would have been motivated to encode and express CNTFRα in a muscle-specific manner in a method of treating ALS because 1) Wang discloses expressing transgenes from muscle provides a good source of therapeutic peptides in vivo; 2) Davis discloses gene therapy to overexpress CNTFα in vivo to treat ALS as a way to focus the neuromuscular protective/regenerating properties of CNTF; and 3) Lee shows muscle-expressed CNTFα is a neuro-regenerating peptide in vivo, and suggests use of muscle-expressed CNTFα may contribute to neuronal regeneration in methods of treating ALS. There would have been a reasonable expectation of success in practicing the claimed invention as all of the claimed elements were known, and the neuro-regenerative properties of muscle-expressed CNTFα had been demonstrated in vivo.
With regard to claims 5-6, and 8-9, Wang discloses wherein the control element comprises a promoter, such as CMV, or inducible, or muscle-specific, such as a murine creatine kinase promoter (paragraphs [0020], [0022], [0101]-[0102]).
With regard to claims 10-13, Wang discloses wherein the AAV vector is administered in a pharmaceutical composition comprising a pharmaceutically acceptable excipient, including one or more dihydric or polyhydric alcohols or sorbitan ester (paragraphs [0123]-[0124]).
With regard to claim 14, Wang discloses the modified AAV vector is administered by intramuscular administration (paragraphs [0130]-[0132]).
With regard to claim 15. Wang discloses the rAAV-based genome is single stranded (paragraph [0007]).
With regard to claim 18, Wang discloses wherein the AAV vector has a serotype selected from AAV 1-AAV 13 (paragraph [0058], Examples 1-4).
Claims 2-4 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2003/0161814 to Wang, further in view of US 5,426,177 to Davis and Lee, 2013, of record, cited on Applicant’s IDS dated 12/21/22 as applied to claims 1, 5-6, 8-15 and 18 above, and further in view of WO2001055172 “WO ‘172”, of record, cited on Applicant’s IDS dated 12/21/22, and Plun-Favreau et al. The Ciliary Neurotrophic Factor Receptor A Component Induces Secretion Of And Is Required For Functional Responses to Cardiotrophin-like Cytokine. The EMBO Journal, 2001. 20(7): 1692-1703. It is noted that WO2001055172 is in French, and an English Translation is provided herein (Elson, 25 pages). Claims 2-4 encompass embodiments wherein the method further comprises administering at least a second AAV vector with enhance skeletal muscle expression, wherein the vector encodes CLC and/or CLF.
The disclosures of Wang, Davis and Lee are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Wang, Davis and Lee combine to render obvious a method of treating ALS comprising an AAV vector with enhanced skeletal muscle expression, wherein the vector encodes CNTFRα. Wang discloses expressing therapeutic genes in muscle cells provides a useful source of recombinant proteins in vivo because skeletal muscle is highly transducible, easily accessible and display low turnover (paragraph [0011]). Wang further discloses the method of treating ALS can comprise administering more than one therapeutic transgene, on the same or different vectors (paragraph [0126]).
In addition, Lee teaches that the exact mechanism utilized by skeletal muscle-expressed CNTFRα that results in its neuro-regenerative effects is not known. Lee posits such effects may be the result of interactions with its endogenous ligands, CNTF or CLC/CLF, as these ligands have been shown to have neuroprotective or neuro-regenerative properties (pages 15-16).
However, none of the cited art teach or suggested utilizing CLC and/or CLF in a gene therapy method comprising recombinant CNTFRα.
WO’172 discloses recombinant CLF (also known as CLF-1, NNT-1 BSF-3), CLC and soluble CNTFRα form a complex with biological activity, function as a CNTF agonist, capable of activating a CNTFR complex on cells expressing gp130 and LIF receptor Beta (Abstract, pages 3, 6-7). Thus WO’172 teaches the CLF/CLC/sCNTFRα complex have activity on any cells that express both gp130 and LIF receptor Beta, and have a role in development of the CNS, survival of central and peripheral nervous system and neuromuscular function (Abstract, page 3, 4, 13, 21 of translation).
WO’172 discloses the complex can be used to treat neurodegenerative diseases for the regeneration of nervous tissue or skeletal muscle via gene therapy (Abstract; page 2, 6-7, 13). WO’172 discloses the genes encoding each of CLF, CLC (NNT1) and soluble CNTFRα are encoded on one or more viral vectors, including an adeno-associated (AAN) virus (pages 6-7, 13-14). WO’172 discloses nucleic acids encoding the genes, spread across one or two vectors can be administered via intramuscular injection to a subject (pages 6-7). WO’172 discloses the formation of a CLF, CLC (NNT) and soluble CNTFRα complex from skeletal muscle would diffuse into the circulation and allow systemic action (page 21). See also claims 1-36.
Plun-Favreau shows the secreted CLC (NNT1) and soluble CNTFRα complex has both neural and motor neural protective properties, capable of reproducing the effect of CNTF in vitro (page 1698, FIG 8A, 8B).
It would have been obvious to combine the method of treating ALS comprising administering an AAV virus with enhanced skeletal muscle expression, wherein the virus encodes CNTFRα and results in the inhibition of motor neuron degeneration of Wang, Davis and Lee, further with the disclosures of WO’172 and Plun-Favreau. A skilled artisan would have been motivated to include an additional AAV vector encoding CLC and/or CLF because Wang discloses expressing therapeutic genes in muscle cells provides a useful source of recombinant proteins in vivo because skeletal muscle is highly transducible, easily accessible and display low turnover, and the method can comprise one or more viral vectors encoding additional transgenes (paragraphs [0011], [0126]). In addition, WO’172 teaches CLC, CLF and soluble CNTFRα form a functional complex that can function as a CNTF agonist, teaches the complex can be used in gene therapy methods of treating ALS, wherein the proteins are secreted from transduced skeletal muscle. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as gene therapy methods comprising skeletal muscle-enhanced expression of therapeutic transgenes was known, and the neuroprotective capabilities of recombinantly expressed soluble CNTFRα, and/or recombinantly expressed CLC, CLF and soluble CNTFRα were known at the time of the invention.
With regard to claim 3, wherein the modified AAV vector and the second modified AAV vector are co-administered, the claim is obvious over Wang, Davis and Lee, further with the disclosures of WO’172 and Plun-Favreau. Wang discloses additional transgenes can be encoded and expressed from additional AAV vectors, but none of Wang, Davis or Lee disclose the timing of administration of another vector encoding a second therapeutic peptide. WO’172 shows CLC (NNT) secretion is dependent on both CLF and CNTFRα expression (soluble or membrane bound) (Example 2, page 19; page 22, FIG 5D). Plun-Favreau acknowledges CLC secretion requires both CLF and CNTFRα expression (page 1692, second column). Plun-Favreau further shows CLC secretion is dependent upon CNTFRα expression (1694, FIG 3 and CLC function required both CLC and CNTFR be expressed from the same cell in order for CLC to form a functional complex (page 1698, first column, FIG 7). Thus, it would have been obvious to co-administer the two AAV viral vectors in order to ensure all proteins were co-expressed for simultaneous expression and secretion.
With regard to claim 4, wherein the modified AAV vector and the second modified AAV vector are administered sequentially, the claim is obvious over Wang, Davis and Lee, further with the disclosures of WO’172 and Plun-Favreau. Wang discloses additional transgenes can be encoded and expressed from additional AAV vectors, but none of Wang, Davis or Lee disclose the timing of administration of another vector encoding a second therapeutic peptide. WO’172 shows CLC (NNT) secretion is dependent on both CLF and CNTFRα expression (soluble or membrane bound) (Example 2, page 19; page 22, FIG 5D). Plun-Favreau acknowledges CLC secretion requires both CLF and CNTFRα expression (page 1692, second column). Plun-Favreau further shows CLC secretion is dependent upon CNTFRα expression (1694, FIG 3 and CLC function required both CLC and CNTFR be expressed from the same cell in order for CLC to form a functional complex (page 1698, first column, FIG 7). Thus, it would have been obvious to administer the two AAV viral vectors sequentially in order to ensure CNTFRα was first expressed, followed by administering the second vector, ensuring all proteins were co-expressed for simultaneous expression and secretion.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2003/0161814 to Wang, further in view of US 5,4261,77 to Davis and Lee, 2013, of record, cited on Applicant’s IDS dated 12/21/22 as applied to claims 1, 5-6, 8-15 and 18 above, and further in view of US Patent Application Publication No. 2012/0232133 to Balazs. Claim 7 is directed to an embodiment wherein the AAV vector with enhanced muscle expression comprises a cytomegalovirus early enhancer element/chicken beta-actin (CAG) promoter operably linked to the CNTFRα transgene.
The disclosures of Wang, Davis and Lee are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Wang, Davis and Lee combine to render obvious a method of treating ALS comprising an AAV vector with enhanced skeletal muscle expression, wherein the vector encodes CNTFRα. Wang discloses expressing therapeutic genes in muscle cells provides a useful source of recombinant proteins in vivo because skeletal muscle is highly transducible, easily accessible and display low turnover (paragraph [0011]). Wang discloses wherein the control element comprises a promoter, such as CMV, or inducible, or muscle-specific, such as a murine creatine kinase promoter (paragraphs [0020], [0022], [0101]-[0102]).
However, none of Wang, Davis or Lee disclose wherein the promoter is a CAG promoter, as required by instant claim 7.
Balazs discloses compact AAV vectors useful for expressing genes encoding therapeutic peptides in vivo (Abstract, paragraph [0008]). Balazs discloses the AAV vectors, formulated as pharmaceutical compositions, are administered to, and infect muscle cells (paragraphs [0172], [0178], [0192]). Balazs discloses the AAV vectors include promoters that drive expression of the therapeutic transgenes in a transduced cell, and such promoters include CMV, a CAG or a UBC promoter (paragraphs [0016], [0086]-[0087], [0103], [0137], [0209]-[0210]). Balazs shows CMV, CAG, UBC or CASI (CASI is a variant of the CAG promoter) promoters provide robust expression of transgene in muscles ([0209]-[0211], FIG 1). Balazs discloses the therapeutic proteins encoded in the AAV vectors include neutrophins, soluble receptors, CNTF, BDNF, GDNF (paragraph [0105]).
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the promoters in the AAV of Wang for a CAG promoter of Balazs because they are all explicitly taught as being useful for driving expression of a transgene, encoded on an AAV, in a muscle cell. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2003/0161814 to Wang, further in view of US 5,426,177 to Davis and Lee, 2013, of record, cited on Applicant’s IDS dated 12/21/22 as applied to claims 1, 5-6, 8-15 and 18 above, and further in view of US Patent Application Publication No. 2015/0152142 to Asokan. Claim 19 is directed to an embodiment wherein the AAV vector with enhanced muscle expression comprises a capsid engineered to direct skeletal muscle expression.
The disclosures of Wang, Davis and Lee are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Wang, Davis and Lee combine to render obvious a method of treating ALS comprising an AAV vector with enhanced skeletal muscle expression, wherein the vector encodes CNTFRα. Wang discloses expressing therapeutic genes in muscle cells provides a useful source of recombinant proteins in vivo because skeletal muscle is highly transducible, easily accessible and display low turnover (paragraph [0011]).
However, none of Wang, Davis or Lee disclose wherein the virus comprises a capsid engineered to direct skeletal muscle expression, as required by instant claim 19.
Asokan discloses recombinant AAV viral vectors with modified capsids that result in enhanced skeletal muscle expression by de-targeting the vector from the liver and/or including a muscle targeting sequence (abstract; [0005]-[0006], [0058], [0082]-[0083], [0226], [0250]-[0253], Examples 5-7). Administered to muscle locally or systemically [0330]-[0332]). Asokan discloses modifying vectors to specific tissue tropism improves their use for gene therapy (paragraphs [0003],[0006], [0008]). Asokan discloses the vectors can be used to treat ALS while being administered to the muscle (paragraphs [0347], [0362]). Asokan discloses the therapeutic proteins encoded in the AAV vectors include neutrophins, soluble receptors, BDNF, GDNF (paragraph [0276]). Asokan discloses the therapeutic peptides can be secreted from the muscle to provide therapeutic benefit systemically (paragraph [0341]).
It would have been obvious to combine the method of treating ALS comprising administering an AAV virus with enhanced skeletal muscle expression, wherein the virus encodes CNTFRα and results in the inhibition of motor neuron degeneration of Wang, Davis and Lee, further with the disclosure of Asokan. A skilled artisan would have been motivated to use the engineered AAV vector of Asokan because Asokan discloses modifying the capsids to improve skeletal muscle tropism improves their use in gene therapy. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as use of AAV vectors comprising capsids engineered for skeletal muscle-enhanced expression was known at the time of the invention.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2003/0161814 to Wang, further in view of US 5,426,177 to Davis and Lee, 2013, of record, cited on Applicant’s IDS dated 12/21/22 as applied to claims 1, 5-6, 8-15 and 18 above, and further in view of Scotter et al. TDP-43 Proteinopathy and ALS: Insights Into Disease Mechanisms and therapeutic Targets. Neurotherapeutics, 2015. 12:352-363. Claim 20 is directed to an embodiment wherein the ALS is characterized by a TDP-43 mutation and/or abnormal TDP-43 distribution.
The disclosures of Wang, Davis and Lee are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Wang, Davis and Lee combine to render obvious a method of treating ALS comprising an AAV vector with enhanced skeletal muscle expression, wherein the vector encodes CNTFRα.
However, none of Wang, Davis or Lee disclose wherein the ALS is characterized by a TDP-43 mutation and/or abnormal TDP-43 distribution, as required by instant claim 20.
Scotter teaches 97% of all ALS cases demonstrate TDP-43 inclusions, regardless of cause (Introduction, pages 352-353). Scotter discloses TDP-43 inclusions spread as ALS progressives (Page 353). Scotter further teaches genetic mutations in TDP-43 account for only 1-2% of total ALS cases (page 353), but the relationship between TDP-43 proteinopathy and ALS remains unknown.
It would have been obvious to combine the method of treating ALS comprising administering an AAV virus with enhanced skeletal muscle expression, wherein the virus encodes CNTFRα and results in the inhibition of motor neuron degeneration of Wang, Davis and Lee, further with the disclosures of Scotter. A skilled artisan would have been motivated to include patients whose ALS is characterized by TDP-43 inclusion because they represent 97% of the total ALS population. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as the presence of TDP-43 inclusions in ALS patients was known at the time of the invention.
Claim Rejections - 35 USC § 112 – 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 16-17 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.
Claims 16 and 17 are drawn to embodiments wherein the method of treating ALS comprising administering an AAV virus with enhanced skeletal muscle expression, wherein the virus encodes CNTFRα and results in the inhibition of motor neuron degeneration of claim 1 “wherein administering the modified AAV vector slows disease progression compared to untreated subjects” and “wherein slowing disease progression comprises at least temporarily partially reversing paralysis.”
The claims are drawn to a broad genus of methods of administering an AAV viral particle effective to result in the claimed functions. However, the claimed methods do not require any specific viral genome, any specific regulatory sequences, any specific CNTFRα gene, no specific viral dosage, no specific route of administration. The claims do not actually require the AAV express the encoded gene. The claims do not define the subject, thus would include both non-human subjects and humans, or disease progression at time of administration.
The specification discloses a few working examples relative to the scope of the invention claimed. The effects of claims 16 and 17 are due to the injection of an AAV vector encoding CNTFRα. Functional results in the specification from the lone injection of an AAV encoding CNTFRα are found in Examples 3 and 11.
Example 3, showing data regarding slowing of disease progressing, tests the same AAV vector over 2 different dosages, with a total of n=11 test subjects. All test subjects were the same age, and had the AAV viruses locally injected in the same two muscles.
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Example 11, showing data regarding motor axons and innervated endplates, tests the same AAV vector over a single dosage, with a total of n=3 test subjects. All test subjects were the same age, and had the AAV viruses locally injected in the same two muscles.
Thus, the total number of mice tested is 14. However, it is not clear whether the n=3 mice from example 11 are actually the same n=3 of the 3x1010vg dosage group of Example 3. In such a scenario, the data representing the scope of the claims stems from 11 mice total.
In addition, with regard to claim 17, wherein there is a temporary reversal of paralysis, the specification shows such a response was seen in 2 treated mice:
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However, the specification does not articulate what dosage these 2 mice received (3x1010vg dosage group or 6x1010vg dosage group). Nor why animals injected with AAV-CNTFRα (3x1010vg dosage max) + AAV-CLC (3x1010vg dosage max) in later Example 12, did not reproduce these results? The results in Example 12 tested 10 mice total, at lowest dose tested in Example 3, but tests an additional 2 lower doses (in combination with AAV-CLC):
The reversal of paralysis occurred in 2/14 =14.2% (at best – if Examples 3 and 11 represent different sample sets), 2/11 = 18.2% (if the data from Example 11 is really from the same mice as Example 3). And, if the data of Example 12 3 x 1010 vg CNTFRa group is added in, 2/17 = 11.8%.
There is no explanation in the specification regarding the reproducibility, or lack thereof, in the test populations, particularly when the efficacy of therapeutic effect is seen with the same or smaller dosages in Example 12.
The structure function relationship between treating ALS and results drawn from animal models is not established in humans. The specification argues the utility of the mouse model used:
[0071] Of the potential ALS treatments developed with SOD1 mutant mice and taken to human trials only riluzole had any clinical benefit. Riluzole modestly slowed both human and mouse disease progression. All other treatments failed to slow mouse or human disease progression, while only delaying mouse disease onset, prompting the conclusion by leaders in the field that recognizing that success at human trial will require slowing of disease progression, the SOD 1-mutant mice have perfectly predicted the success of riluzole and the failure of efficacy of each other drug attempted in human trial. Therefore, despite the examples of failed ALS treatments developed with SOD1-mutant mice, the assay is completely valid when used correctly to measure changes in disease progression.
[0072] Moreover, it is not enough that treatments slow disease progression. Late ALS symptom onset and subsequent, long delays in clinical diagnosis before treatment initiation dictate that any broadly useful ALS treatment must be effective when initiated very late in the underlying disease.
While the Examiner cannot validate or discredit Applicant’s blanket statement, the consensus in the art recognizes the value of animal models in the investigation of the pathophysiology of ALS, and their use in development of therapeutic strategies and targets. However, as the understanding of the pathophysiology of the disease progresses, identifying multiple genetic causes and complex and overlapping disease progression, data generated from animal models has become less applicable.
Until recently there has been over-reliance on the SOD1G93A transgenic mouse model of ALS. This is a very useful model which replicates many of the clinical and pathological features of ALS. However, only 2% of patients with ALS have a SOD1 mutation, and unlike the disease in most patients with ALS, SOD1-mediated disease is not a TDP-43 proteinopathy. The field is now learning to use the SOD1-transgenic mouse more appropriately, but an ongoing challenge is that murine models of other genetic subtypes of ALS have current limitations for therapeutic testing. The field is also now recognizing that more careful attention needs to be directed to the whole translational pathway from preclinical study design to early demonstration of target engagement in patients. See, page 202 in Mead, 2023. Internal citations deleted.
Indeed, Mead 2023 also discloses significant additional work is needed, even after positive data is identified using a mouse model, in order to improve the predictability from animal to humans:
It is now possible to develop preclinical screening cascades which take us far beyond unreliable readouts of survival in SOD1-transgenic mice. A combined approached can be used, with target-specific screening in vitro validated early in orthogonal patientderived cell assays for selected compounds. SOD1-transgenic rodents can be used for early mechanistic pharmacokinetic–pharmacodynamic work, followed by studies focused on evaluating more global effects on motor system degeneration. Finally, validation in alternative model systems such as patient-derived in vitro models and more physiologically relevant mouse models should enhance confidence in clinical translatability. Such an approach should enable a step-change in our ability to predict therapeutic efficacy in the clinic (Fig. 3).
Vas-Cath Inc. V. Mahurkar, 19USPQ2d 1111, clearly states "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).
The written description requirement is in place to ensure that “when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function.” Ariad Pharms. Co. v. Eli Lilly & Co., 94 U.S.P.Q.2d 1161, 1172 (Fed. Cir. 2010) (en banc). The working examples reflect a small scope of the protection sought. In addition, the specification does not permit the skilled artisan to visualize all of the members of the genus being administered in the claimed methods or the manner in which they are administered, which would predictably result in the claimed effects.
If claims merely recite a “description of the problem to be solved while claiming all solutions to it” and “cover any compound later actually invented and determined to fall within the claim’s functional boundaries,” they have not met the description requirement. Ariad, 94 U.S.P.Q.2d at 1172. Such is the case here, especially given the fact that applicants’ disclosure contains only 2 examples of the claimed method, i.e. “a mere mention of a desired outcome.” Id. at 1176. Applicant might overcome this rejection by establishing that the art recognizes a correlation between the structure of the viruses administered in the claim and their function. Id. at 1171.
Applicants’ disclosure appears to be an investigation of a mechanism ALS is treated with CNTFRα. However, [p]atents are not awarded for academic theories, no matter how groundbreaking or necessary to the later patentable inventions of others.” Ariad, 94 U.S.P.Q.2d at 1173. The patent system is designed to give incentives to complete inventions, not to guess at the future. Id. at 1174.
Therefore, the claimed methods have not met the written description provision of 35 U.S.C. $112, first paragraph. 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).
Conclusion
No claims are allowed.
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KAA
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633