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 amendments to the claims dated 5/06/26 are acknowledged. Claims 1-20 are pending and subject to prosecution. Claims 1, 2, 17 and 19 are amended. The 1.132 Declaration on behalf of Alexander John MacLennan, of record 5/06/2026 is acknowledged.
CLAIMS
Independent claim 1, of record 5/06/26 is presented below:
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Amended claim 1 recites, at least, “A method for slowing progression of amyotrophic lateral sclerosis (ALS) in an adult subject … comprising: inhibiting motor neuron degeneration by administering to the subject, after onset of ALS symptoms, a modified adeno-associated virus (AAV) vector… comprising … a transgene consisting essentially of a ciliary neurotrophic factor receptor alpha (CNTFRα) cDNA insert, wherein the modified AAV vector is engineered to increase skeletal muscle expression of CNTFRα relative to the level of CNTFRα expression otherwise present without the AAV administration.
Thus, the claims, as amended, require inhibiting motor neuron degeneration by administering [a rAAV vector encoding a CNTFRα transgene] to the adult subject, “after onset of ALS symptoms.” The specification does not actually define “onset of ALS symptoms” or “ALS symptoms.” Paragraphs [0042] and [0067], respectively, of the published specification discuss “symptoms” of ALS. Including symptoms associated with “early,” “middle” and “late” stages, :
ALS is characterized by stages progressing in severity. In early stage ALS disease, muscles may be weak and soft or stiff, tight, and spastic. Muscle cramping and twitching occurs, as does loss of muscle bulk. Symptoms may be limited to a single body region or mild symptoms may affect more than one region. The subject suffering from ALS may experience fatigue, poor balance, slurred words, weak grip, tripping, or other minor symptoms. Middle stage ALS is characterized by more widespread symptoms, muscle paralysis, or muscle weakening. Cramping and twitching may also be present. Unused muscles may cause contractures, whereby joints may become rigid, painful, and deformed. Weakness in swallowing muscles may cause choking and difficulties eating. Weakened breathing muscles can lead to respiratory insufficiency, particularly when lying prone. Subjects may also experience inappropriate laughing or crying (pseudobulbar affect). In late stage ALS, most voluntary muscles are paralyzed. Respiratory muscles are severely compromised. Mobility is limited and assistance is required for personal care. Poor respiration may cause fatigue, confusion, headaches, and pneumonia. Speech, eating, and drinking may not be possible. In certain embodiments, the modified AAV gene delivery vectors packaging rAAV genomes comprising cDNA inserts described herein are useful in treating a subject suffering from ALS. In a specific embodiment, the modified AAV vectors are useful in treating subjects suffering from early, middle, or late stage ALS. In a very specific embodiment, the modified AAV vectors are useful in treating late stage ALS disease. [0042]
Mice were monitored for weight and inability to right themselves in 30 sec when placed on side, i.e., -universal index of end stage paralysis (loss of motor function) in ALS mouse models. These data, and age at max weight, age at 10% weight loss from max, and time from max weight to end stage (widely used indexes of disease onset, early disease and disease duration, respectively) were analyzed by 2-tailed log rank test. [0067]
The working examples used two ALS mouse models, the SOD1G93A Mouse and the TDP-43Q331K Mouse. Paragraph [0067] discloses the parameters that were used to define disease onset, early disease and disease duration, respectively, in the mice utilized in the working examples. However, such a teaching is not a limiting definition of onset of ALS symptoms in mouse models of ALS or other treated subjects.
At the time of filing, ALS symptom onset in SOD1G93A mice had recently been reevaluated. While the use of SOD1G93A Mouse Model of ALS was well known, the model had not translated into successful human clinical trials. Multiple publications had noted that what investigators generally identify as disease onset of ALS (motor deficit, ALS symptoms) in these mice occurs significantly later (about day 90/13 weeks) in life than the pathological changes associated with ALS identified in the mice (such as loss of muscle innervation), and such disparity is likely one factor as to why results seen in the SOD1G93A mice had not translated into successful human clinical trials (Vinsant, 2013a; Vinsant, 2013b; Gerber, 2012; Mancuso, 2011; Mead, 2011; Hayworth, 2009). Traditional methods used to measure/determine ALS motor deficit were considered insensitive, and asserted as unable to detect subtle motor deficit changes occurring earlier than about day 90/13 weeks (Mancuso, 2011; Vinsant, 2013b; Hayworth, 2009). As a result, additional analysis of ALS symptom onset in SOD1G93A mice using new techniques identified ALS symptoms occur much earlier in life than day 90 (~13 weeks). Mancuso, 2011 identified motor deficit in SOD1G93A mice at about 8 weeks (~ day 56) analyzing paw placement in treadmill locomotion. Gerber, 2012 identified motor deficit at day 60 (~ 8 weeks) analyzing front limb and hind limb placement over a single step in an open field. And, Vinsant, 2013b showed ALS disease symptoms in SOD1G93A mice as early as postnatal days 30 to 40 (~ 4 weeks), exhibited by loss of muscle strength measured by loaded grid test, and variability of gait using an uphill treadmill walking protocol (page 444; FIG 23; FIG 24, Vinsant, 2013b).
Vinsant, 2013b states,
Traditionally, disease onset was considered to occur in the third postnatal month, a time coincident with detection of MN cell death; however, here we also provide evidence that motor function deficits begin coincident with initial muscle denervation. Muscle strength, as assessed by the loaded grid test and treadmill gait was impaired in mutant mice beginning around P30–40 and treadmill deficits only occurred in mice walking uphill at increased speeds when the TA muscle is increasingly engaged (Roy et al. 1991). Symptom onset would be expected to occur when pathological and motor function deficits are evident, and therefore in the SOD1G93A mouse, symptom onset must be considered to occur at P30, rather than at P70–90 as commonly reported … We propose that P30 therefore represents a more realistic approximation of symptom onset in mutant mice and therefore a reevaluation of previous preclinical studies for ALS should be considered in light of this. Indeed, studies where treatment of SOD1 mutant mice was begun at P30 or earlier demonstrated some of the most effective survival promoting effects reported (Kieran et al. 2005; Pun et al. 2006; Gifondorwa et al. 2007). (See text on pages 444-446).
Thus, at the time of filing, ALS symptom onset in SOD1G93A mice would necessarily be present as of day 30 (week 4).
In addition, disease onset of ALS in the TDP-43Q331K Mouse occurs at 3 to 10 months of age, identified by tremor or declining rotarod performance, with earlier onset seen with increased TDP-43Q331K expression (last paragraph page E737 – first paragraph page E738; Arnold, 2013).
Thus, interpretation of the claimed requirement wherein the virus is administered to an adult subject, “after onset of ALS symptoms” incudes after the subject exhibit any stage symptom (per paragraph [0042] of the published specification), and necessarily at day 30 in a SOD1G93A Mouse (per Vinsant, 2013b) or around 3 to 10 months in a TDP-43Q331K Mouse (per Arnold, 2013).
STATUS OF OBJECTIONS/REJECTIONS OF RECORD AND RESPONSE TO ARGUMENTS
Objection of Claim 19:
The objection over claim 19 is WITHDRAWN in light of Applicant’s amendment to claim 19.
112(b) Rejection of Claims 1-20:
The 112(b) rejection over claims 1 and 2 for reciting “enhanced” expression is WITHDRAWN in light of Applicant’s amendments to claims 1 and 2 which now recite “increased” expression.
The 112(b) rejection over claim 17 for reciting “temporarily partially reversing paralysis” is WITHDRAWN in light of Applicant’s amendments to the claim and in consideration of Applicant’s arguments. Claim 17 has been amended to recite “at least temporarilymotor symptoms associated with ALS
As such, the 112(b) rejection over claims 1-20 is WITHDRAWN.
103 rejections of the claims:
Rejection of claims 1, 5-6, 8-15 and 18 as obvious over U.S. Patent Application Publication No. 2003/0161814 to Wang, in view of U.S. Patent No. 5,426,177 to Davis, and Lee, 2013 of record;
Rejection of claims 2-4 as obvious over Wang, Davis and Lee, further in view of WO2001/055172 and Plun-Favreau, 2001;
Rejection of claim 7 as obvious over Wang, Davis, and Lee, further in view of U.S. Patent Application Publication No. 2012/0232133 to Balazs;
Rejection of claim 19 as obvious over Wang, Davis, and Lee, further in view of U.S. Patent Application Publication No. 2015/0152142 to Asokan;
and
Rejection of claim 20 as obvious over Wang, Davis, and Lee, further in view of Scotter, 2015:
The 103 rejection over Wang, Davis and Lee is WITHDRAWN in light of Applicant’s amendments to the claims. The amendment to claim 1, which requires wherein the method is administered to a subject after onset of ALS symptoms, is sufficient to overcome the rejection. Wang administers the AAV-GDNF vectors to the SOD1G93A mice at 9 weeks of age (thus, approximately day 70) when tested with a rotarod, where Wang’s experiments defined disease onset “as the time when the mouse could not remain on the rotarod for 7 minutes at a speed of 20 rpm” (paragraph [0156]). However, as evidenced by Vinsant, 2013b cited above, SOD1G93A mice necessarily exhibit symptoms of ALS by day 30 when tested by loaded grid test and treadmill gait. Because Wang does not identify the 9 week old SOD1G93A mice were administered the vector “after onset of ALS symptoms” the rejection is withdrawn. However, a new the rejection showing the mice of Wang were administered the AAV-GDNF after onset of symptoms, as evidenced by Vinsant, 2013b, is presented.
Applicant’s arguments with respect to the 103 rejections of record have been considered but are not fully persuasive and are addressed for completeness of record. In addition, arguments regarding the 103 rejection of record asserted in the Declaration on behalf of Dr. MacLennan are also addressed herein. Applicant argues that the claims are not obvious over Wang, Davis, and Lee at least because none of the cited art discloses treating ALS after the onset of symptoms, and because there would be no expectation of success in arriving at the results demonstrated in the specification and/or disclosed in the 1.132 Declaration on behalf of Dr. MacLennan, of record 5/06/2026.
With regard to the prior art, Applicant argues Wang does not administer to mice after onset of ALS symptoms, arguing Wang admits to treating mice before disease onset (page 8 of the Reply). Applicant further argues neither Davis nor Lee treat ALS after onset of symptoms, where “Davis merely speculated about CNTF in ALS based on its ability to inhibit motor neuron degeneration” and Lee “offers only speculative language about potential relevance to ALS” (page 8 of the Reply).
At Page 8 of the Reply Applicant states:
“Wang explicitly treated mice before symptom onset (see, e.g., para. [0186]) and showed that, although treatment delayed symptom appearance, it did not alter disease progression after onset. Specifically, at para. [0187], Wang reported that "the number of days that elapsed from the onset to the end Stage, did not differ between the AAV-GDNF vector-treated and control ALS mice." Further, Wang et al., in their 2002 paper, of record, admitted "...transgenic GDNF only exhibits its protective function for motoneurons in ALS mice at asymptomatic stages .... Once the disease develops, however, GDNF gene therapy cannot effectively ... interfere with the rapidly inevitable progression of the disease." (p. 6927, para. 4, emphasis added). The authors acknowledged that neurotrophic therapies were ineffective after ALS became symptomatic. (Declaration, para. 6, emphasis added).
The Examiner is not convinced of error. With regard to Applicant’s arguments alleging Wang does not administer AAV-GDNF to SOD1G93A mice with ALS symptoms, mirrored in the Declaration at paragraph 6, the Examiner cannot agree. Wang administered the AAV-GDNF vectors to the SOD1G93A mice at 9 weeks of age (thus, approximately postnatal day 70) when tested with a rotarod, where Wang’s experiments defined disease onset “as the time when the mouse could not remain on the rotarod for 7 minutes at a speed of 20 rpm” (paragraph [0156]). However, as evidenced by Vinsant, 2013b cited above, SOD1G93A mice exhibit symptoms of ALS by day 30. As such, the 9 week old SOD1G93A mice of Wang necessarily exhibited onset of ALS symptoms before they were administered the AAV-GDNF. The fact that Wang’s “defined” onset of symptoms is a different ALS symptom than other known earlier symptoms of ALS in the SOD1G93A mice does not mean that the 9 week old SOD1G93A were not symptomatic of ALS.
Indeed, Vinsant, 2013b, considers the earlier onset of ALS symptoms in the mice “represents a more realistic approximation of symptom onset in mutant mice” and “a reevaluation of previous preclinical studies for ALS should be considered in light of this” (pages 444-446).
At page 8 of the reply, Applicant argues that Wang admits the mice were treated before symptoms in a 2002 paper “of record”, mirrored in the Declaration at Paragraph 6. However, the Examiner is unable to find this reference cited on the one IDS of record (12/21/2022), nor is this reference cited by the Examiner in the non-final rejection. Thus, any arguments dependent upon Wang’s 2002 paper are not persuasive. Regardless, given the disclosure of newly identified Vinsant, 2013b showing SOD1G93A mice exhibit symptoms of ALS by day 30, or Mancuso, 2011 showing motor deficit in SOD1G93A mice at about 8 weeks, or Gerber, 2012 identified motor deficit at day 60 this argument is not persuasive.
Applicant’s argument, mirrored in Declaration paragraph 6, that the treatment in Wang “delayed symptom appearance” but “did not alter disease progression after onset” does not undermine Wang’s relevance to the pending claims. While the preamble of the claim is directed to “A method for slowing progression of amyotrophic lateral sclerosis (ALS) in an adult subject” the body of the claim itself does not require altering or slowing disease progression, nor does the specification define “slowing progression” of ALS.
M.P.E.P. § 2111.02 reads, “The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "‘extraneous’ limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.”
As such, art which demonstrates or renders obvious “inhibition of motor neuron degeneration” as required in the body of the claim following administering an AAV encoding CNTFRα, would read on the claimed preamble of “slowing progression” of ALS. Indeed, Wang, as evidenced by Vinsant, 2013b showed 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]) as claimed. As such, Wang, as evidenced by Vinsant 2013b discloses treatment of ALS in an adult by inhibiting motor neuron degeneration by administering the AAV vector encoding a neurotrophic factor after disease onset as required by claim 1. Davis and Lee are relied upon as rendering obvious encoding CNTFRα in the AAV vector of Wang, resulting in inhibition of motor neuron degeneration.
In addition, the Examiner disagrees that Wang’s disclosure at paragraph [0005] teaches away from the therapeutic use of neurotrophic factors to treat ALS. Wang’s disclosure at paragraph [0005] discloses delivery of the neurotrophic factors via gene therapy represents a therapeutic pathway to overcome the short life and inflammatory responses seen from administering the neurotrophic factors as peptides seen in clinical trials, and paragraph [0006] introduces AAV as a viable gene therapy option for the sustained delivery of the neurotrophic peptide:
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Applicant’s arguments, mirrored in Declaration paragraphs 7 and 8, that neither Davis nor Lee treat ALS after onset of symptoms, where “Davis merely speculated about CNTF in ALS based on its ability to inhibit motor neuron degeneration” and Lee “offers only speculative language about potential relevance to ALS” (page 8 of the Reply) are not persuasive.
Applicant’s assertion that Davis “merely speculated about CNTF in ALS based on its ability to inhibit motor neuron degeneration” does not undermine the rejection with respect to the scope of the claims, and ignores the disclosures relied upon in the rejection, when considered in the light of the combination of Wang, Davis, and Lee. Applicant’s argument that Davis merely “speculated” on its use in methods of treatment of ALS based on its ability to inhibit motor neuron degeneration is simply saying without reduction to practice, there would be no expectation of success in expressing recombinant CNTFRα from the AAV vectors of Wang in an ALS patient exhibiting some ALS symptom, which would result in some amount of inhibition of motor neuron degeneration of some motor neurons. However, conclusive proof of efficacy is not required to show a reasonable expectation of success. Obviousness does not require absolute predictability, but at least some degree of predictability is required. MPEP 2143.02.
The rejection recognizes that Davis does not reduce the disclosed compositions or methods to practice. However, the rejection articulates how 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).
Applicant’s arguments that Lee “offers only speculative language about potential relevance to ALS” and that a skilled artisan would recognize that nerve lesion model, rather than ALS, involve fundamentally different mechanisms (page 8 of the Reply) are also not persuasive.
Applicant’s assertion that Lee does not use CNTFRα in a method of ALS does not undermine the rejection with respect to the scope of the claims, and ignores the disclosures relied upon in the rejection, when considered in the light of the combination of Wang, Davis, and Lee. Applicant’s argument that Lee merely “speculated” on its use in methods of treatment of ALS (i.e., does not reduce to practice), there would be no expectation of success in expressing recombinant CNTFRα from the AAV vectors of Wang in an ALS patient exhibiting some ALS symptom which would result in some inhibition of motor neuron degeneration some motor neurons. However, conclusive proof of efficacy is not required to show a reasonable expectation of success. Obviousness does not require absolute predictability, but at least some degree of predictability is required. MPEP 2143.02.
The rejection sets forth the rationale for using CNTFRα in ALS, based on the specific text of Lee, who 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.
Applicant’s argument that a skilled artisan would recognize that nerve lesion model, rather than ALS, involve fundamentally different mechanisms is also not persuasive. Lee explicitly acknowledges a skilled artisan, seeing the neuroregenerative properties resulting from CNTFRα expression generated from the nerve lesion would consider its use to treat ALS.
In paragraph 8 of the Declaration, Dr. MacLennan argues, “a skilled artisan would have expected increased CNTF signaling through CNTFRα upregulation to cause the same unacceptable side effects previously observed with CNTF administration – side effects that Applicants surprisingly did not observe. The Examiner notes that Dr. MacLennan fails to identify which unacceptable side effects were not observed, so the argument is not persuasive. However, Wang’s disclosure at paragraph [0005] discloses delivery of the neurotrophic factors via gene therapy represents a therapeutic pathway to overcome the short life and inflammatory responses seen from administering the neurotrophic factors, including CNTF, as peptides seen in clinical trials, and paragraph [0006] introduces AAV as a viable gene therapy option for the sustained delivery of the neurotrophic peptide. Thus, Wang’s methodology is specifically addressing known side-effects which caused cessation of clinical trials.
At page 10 of the Reply, Applicant argues improper hindsight. The Examiner is not persuaded. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Wang, as evidenced by Vinsant, 2013b 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 after onset of ALS symptoms, 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. 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 CNTFRα 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 CNTFRα to the patient, and expressing the CNTFRα in appropriate cells (column 27, line 3- column 28, line 5; column 36, lines 10-17). And, Lee shows muscle-expressed CNTFRα is a neuro-regenerating peptide in vivo, and suggests use of muscle-expressed CNTFRα may contribute to neuronal regeneration in methods of treating ALS.
Also at page 10 of the Reply, Applicant argues there would be no motivation to choose CNTFRα for further development (citing to Otsuka, 678, Federal Circuit, 2012) from the disclosure of Wang, because Wang notes clinical trials of repeated administration of neurotrophic factors, such as CTNF, have shown limited or no promise and/or have results in severe side effects at paragraph [0005]). The Examiner is not persuaded. Initially, Applicant’s use of Otsuka is confusing and non-persuasive. Otsuka’s test is whether there is motivation to modify a lead compound to make the claimed compound. This is not the fact pattern of the disclosure of Wang, or the reasoning of the rejection. The rejection lays out that Wang establishes a method of administering AAV vectors encoding a neurotrophic factor, such as GDNF or CTNF, to a subject with ALS. Davis and Lee are used for introducing vectors encoding the neurotrophic factor CTNFRα and its therapeutic role in ALS/motor nerve regeneration. There is no suggestion that the GDNF is modified into CNTFRα, thus there is no suggestion of a lead compound be modified into a claimed compound.
With regard to Applicant’s argument that there is no expectation of success of practicing the claimed invention from the combination of art, the Examiner is not convinced of error. At pages 7-8 of the Reply, Applicant points to the 1.132 Declaration on behalf of Dr. MacLennan to support the argument that there would have been no expectation of success of slowing the progression of ALS in a subject already exhibiting symptoms of ALS by increasing skeletal muscle CNTFRα from the combination of Wang, Davis and Lee. At page 7, Applicant argues:
“As described in paragraph 4 of the Declaration, ALS is characterized by a gradual degeneration of motor neurons, with substantial pathological damage occurring before overt symptoms arise. In clinical practice, diagnosis and treatment almost always occur after overt symptom onset. Dr. MacLennan states ‘at the time of filing of the application, the ALS research literature indicated that, while some treatments were effective at slowing ALS progression if started before or at overt symptom onset, none were effective if started after overt symptom onset, as clinically required. Consequently, any treatment shown to be effective when initiated after overt symptom onset would have been considered unexpected and clinically significant.’”
The Examiner is not persuaded. Initially, the reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. Conclusive proof of efficacy is not required to show a reasonable expectation of success. Obviousness does not require absolute predictability, but at least some degree of predictability is required. MPEP 2143.02.
Claim 1 requires administering to a subject already exhibiting (after) onset of ALS symptoms, an AAV encoding CNTFRα, wherein the AAV vector is engineered to increase skeletal muscle expression of CNTFRα, relative to the level of CNTFRα otherwise present in the cell, wherein the method results in the inhibition of motor neuron degeneration. The claim nor specification limit the subject, define the ALS symptom exhibited, identify the type or degree of motor neuron degeneration that is inhibited, and technically, the claim does not require the CNTFRα transgene encoded on the AAV is actually expressed in skeletal muscle (“engineered to increase”).
Dr. MacLennan’s Declaration, at paragraph 4, asserts that at the time of filing, no therapeutically effective treatments have been shown when beginning treatment after overt symptoms of ALS occur, made in an attempt to show, in part, there would be no expectation of success in practicing the claimed invention from the cited prior art. Initially, Dr. MacLennan’s statements regarding ALS research at the time of filing in paragraph 4 does not cite to any specific published literature. As such, such statements in this section can only be considered opinion evidence. (MPEP 716.01(c)).
Regardless, Dr. MacLennan’s use of the term “overt symptom” of ALS appears synonymous with “symptom” of ALS. The broadest reasonable interpretation of “overt symptom” of ALS appears synonymous with “symptom”, and thus is reasonably interpreted as any symptom exhibited any stage (early, middle or late) symptom in a human or mouse (per paragraphs [0042] or [0067] of the instant specification), and including ALS symptoms at day 30 in a SOD1G93A Mouse (per Vinsant, 2013b) or ALS symptoms of around 3 months in a TDP-43Q331K Mouse (per Arnold, 2013), as articulated in the CLAIM section above.
In addition, Dr. MacLennan’s assertion that while there may be prior art showing effective therapies before or “at overt onset of symptoms”, no prior art exists that were effective if started “after” overt symptom onset is not persuasive. Neither the specification, working examples, Declaration, nor prior art define how much time is required between identification of an overt symptom of ALS and beginning of treatment in order to distinguish beginning treatment “at onset” from beginning treatment “after overt symptom onset.” The broadest reasonable interpretation of administering “after” symptom onset is any amount of time once the ALS symptom is apparent – whether the time is a minute after, an hour after, a day after, a week after, a month after, etc..
For example, the specification, working examples, and the Declaration identify embodiments of beginning treatment “after onset”, but none differentiate at what point treatment “at onset” differs from “after onset”:
Paragraph [0057] teaches “In some embodiments, administration of one or more AAV vectors as described herein is initiated prior to, contemporaneous with, or even after onset of motor neuron symptoms in the subject. In a specific embodiment, administration is initiated during late stage ALS disease…”
Paragraph [0067] teaches, “Mice were monitored for weight and inability to right themselves in 30 sec when placed on side, i.e., -universal index of end stage paralysis (loss of motor function) in ALS mouse models. These data, and age at max weight, age at 10% weight loss from max, and time from max weight to end stage (widely used indexes of disease onset, early disease and disease duration, respectively) were analyzed by 2-tailed log rank test.”
Examples 3, 11, and 12 shows administration an AAV1.1-CNTFRα vector injected unilaterally into lateral gastrocnemius and soleus muscles of SOD1G93A mice at days 120-130, which is “after onset of ALS symptoms” (paragraphs [0074]-[0075]; [0094], [0099]-[0100]; FIGs. 2A-2E; FIG. 8; FIGs. 9A-9B).
At Paragraph 10 of the Declaration, Dr. MacLennan shows administration of 3 x 1010 vg (n=21) of an AAV1.1-CNTFRα injected unilaterally into lateral gastrocnemius and soleus muscles of SOD1G93A mice at day 120.
At Paragraph 12 of the Declaration, Dr. MacLennan carries out additional experiments as those described in Example 11, and shows administration of 3 x 1010 vg (n=5) of an AAV1.1-CNTFRα injected unilaterally into lateral gastrocnemius and soleus muscles of SOD1G93A mice at day 120.
At Paragraphs 15-16 of the Declaration, Dr. MacLennan tests two AAV-CNTFRα vectors in TDP-43Q331K mice. Dr. MacLennan administered the AAV1.1-CNTFRα vector (used previously) (n=9) as well as an AAV1-tMCK-skCRM4-CNTFRα vector (n=21) to the TDP-43Q331K mice. “The same AAV treatment procedure was initiated after overt symptom onset (after 3 weeks of declining rotarod performance) to be clinically relevant” (paragraph 15). The data of these experiments is presented in FIG. E of the Declaration. The specific dosages administered in these experiments is presented in the figure text; however, the figure text is illegible, and thus specific dosages are not known.
In addition, contrary to Dr. MacLennan’s assertion, the prior art identifies examples of effective treatments of ALS when treatment is initiated after onset of ALS symptoms – either purposefully by first identifying the disease onset and then initiating treatment, or inherently, wherein treatment is initiated in an ALS animal model at a time point later than the model is known for already exhibiting symptoms of ALS:
Pandya, 2013 presents a review of therapeutic agents used for treatment, prevention or the further elucidation of ALS pathophysiology/disease as of 2013. At Table 1, Pandaya identifies multiple published studies of agents tested for efficacy in SOD1G93A ALS mice models, where the treatment is administered “preventively” or “therapeutically.” Pandya teaches “preventively” indicates that the intervention started before symptom onset, whereas “therapeutically” indicates that the intervention began at or after symptom onset (page 4733). Pandaya indicates timing of initiation of treatment at symptom onset or after onset in mouse models mimic the clinical treatment of ALS in patients (page 4730).
The Examiner notes the studies on SOD1G93A mice, identified in Pandaya disclosing either preventative or therapeutic interventions, defined by administration of before onset, at onset, or after onset, may actually be performed on SOD1G93A mice after day 30, in which case the methods are actually performed “after onset of ALS symptoms” as evidenced by Vinsant, 2013b. For example, Crow, 2005, cited in Pandaya (ref. 111 therein) discloses treatment of SOD1G93A mice with manganese porphyrin (AEOL10150) have increased numbers of spinal cord motor neurons and increased survival of treated ALS mice compared to controls (Abstract, FIGs. 2, 3; Table). Treatment showed protection from motor neuron degeneration (FIG. 4A), and mice retained motor neuron function through end-stage disease (page 262, Table). Crow discloses the method administers AEOL10150 “at symptom onset” (abstract) or more specifically, “on the first day of visible muscle weakness” page 259, or “the first day of symptom onset” (page 260). Crow’s method comprises first determining onset of symptoms each individual SOD1G93A mouse, wherein onset of symptoms is defined as the first day of altered hindlimb gait (page 260). Only once a mouse was determined to demonstrate onset of symptoms is the mouse treated. “Mice were randomized into control and treated groups based on onset; the first mouse to show signs was placed in the control group, the second was inject and placed in the treated group, and so on in an alternating manner” (page 260). Thus, Crow discloses a method wherein a therapeutic agent is administered “after onset of ALS symptoms” which results in the inhibition of motor neuron degeneration.
The interpretation of Crow’s methodology, identified therein as initiating treated “at symptom onset” as initiation of treatment “after onset of symptoms” in light of Crow’s step-wise methodology wherein mice exhibiting ALS symptoms are first identified and treatment is administered after identification, is supported by the prior art. Kim, 2006 shows administration of the cannabinoid receptor agonist AM1241 to SOD1G93A mice is effective to slow disease progression in mice when administered “after onset of signs” in the mice (Abstract). Kim discloses administering AM1241 to SOD1G93A mice beginning at day 75, after mice were observed with tremors. Kim states, “hSOD1G93A mice were administered AM1241 (1 mg/kg body weight) or vehicle beginning at 75 days of age, when tremors were first observed., i.e., after onset of disease…The earliest clinical signs of disease observed were tremors and shaking in their limbs when mice were suspended briefly in the air by their tails. These signs were never seen in non-transgenic littermates, but were always seen in hSOD1G93A mice after 75 days” (page 103, internal citations omitted). Kim references the administration of AM1241 throughout the disclosure as “after onset” (Abstract, pages 101, 103).
Henriques, 2010 presents a review of neurotrophic growth factors used for treatment, prevention or the further elucidation of ALS pathophysiology/disease as of 2010. At Tables 1 and 2, Henriques identifies multiple published studies of neurotrophic growth factors tested for efficacy in SOD1G93A ALS mice or rodent models, where the treatment is administered “presymptomatically” or “symptomatic” or “onset.”
The Examiner notes the studies on SOD1G93A mice, identified in Henriques disclosing either presymptomatic, symptomatic, or onset, may actually be performed on SOD1G93A mice after day 30, in which case the methods are actually performed “after onset of ALS symptoms” as evidenced by Vinsant, 2013b. For example, Ishigaki, 2007 (cited in Henriques) discloses intrathecal delivery of recombinant hepatocyte growth factor (HGF) for 4 weeks to SOD1G93A rats starting at day 100 (the age at which pathological changes appear but animals display no clinical weakness) and starting at day 115 (onset of paralysis). Ishigaki notes the defined onset of ALS used in the study (first observation of abnormal gait and limb weakness which indicate onset of paralysis) is “not a sensitive indicator [of disease onset] and appears later than the decrease in activity” seen in the rats – which is a different ALS symptom (page 1038, first column, ref. 10). Thus, Ishigaki acknowledges the SOD1G93A rats at day 115 already display an ALS symptom, just not the ALS symptom he uses as baseline during his experiments. Ishigaki notes administration of HGF at day 115 reduces motor neuron degeneration and slowed progression of the disease (Abstract, FIG 3). Thus, Ishigaki discloses a method wherein a therapeutic agent is administered “after onset of ALS symptoms” which results in the inhibition of motor neuron degeneration.
Dodge, 2008, (cited in Henriques) administers an AAV vector encoding IGF1 (AAV-IGF-1) to SOD1G93A mice at day 88-90, “at disease onset” (page 1057, second column). Dodge shows motor neuron function is evaluated at day 80 (i.e. before administration) and then weekly after (days 90, 100, 110, etc.) (FIGs. 3a-3b). The mice of days 88-90 were necessarily exhibiting signs of ALS prior to administration, as SOD1G93A mice exhibit ALS symptoms as of day 30 (as evidenced by Vinsant, 2013b). Dodge shows administration of AAV-IGF-1 to the SOD1G93A mice slows progression of ALS, and “reduced ALS neuropathology, improved muscle strength, and significantly extended life span in ALS mice” (Abstract). Dodge shows AAV-IGF-1 inhibited motor neuron degeneration (FIG 2), improved muscle strength (FIGs 3a-3c), reduced ALS neuropathology (FIGs. 5-6).
Kaspar, 2003, (cited in Henriques) administers AAV-IGF-1 or AAV-GDNF to SOD1G93A mice to muscle at day 60 “before disease onset” or at day 90 “at the time of disease onset” (page 839). The SOD1G93A ALS mice of days 60 and day 90 were necessarily exhibiting signs of ALS prior to administration, as SOD1G93A mice exhibit ALS symptoms as of day 30 (as evidenced by Vinsant, 2013b). Kaspar discloses both IGF-1 and GDNF mice treated at 60 days or 90 days showed increased survival compared to ALS controls (page 839, FIG. 1F, 2A). Kaspar discloses SOD1G93A ALS mice, treated with AAV-IGF-1 at 90 days, displayed improved neuromuscular function compare to ALS controls, evidenced by grip strength and rotarod performance (FIGs. 2B-2D), displayed increased muscle mass compared to controls (FIG. 2E). Kaspar states, “These combined results suggest that addition of IGF-1 after the onset of overt motor dysfunction results not only in an extension of life but also in a delay in the functional decline associated with the disease” (page 839). Kaspar also shows SOD1G93A ALS mice, treated with AAV-IGF-1 at 90 days, had increased numbers of motor neurons compared to untreated SOD1G93A ALS mice throughout disease progression (FIG. 3). Kaspar states, “We describe AAV-NTF delivery in vivo to the hindlimb and intercostal muscles in a mouse model of ALS, which results in a significant delay in the decline of motor function, a prolongation of MN survival, a decrease in parenchymal gliosis, and most importantly, a prolongation in survival. Furthermore, these effects were evident even with late delivery of therapy—at the time of symptom onset—that is comparable to the method and time of treatment that needs to be used for the human disease” (page 841).
Azzouz, 2014 (cited in Henriques) administers lentiviral EIAV vectors encoding VEGF to SOD1G93A mice muscle at day 21 “before” onset or at day 90 “at onset” (page 414). The SOD1G93A ALS mice of day 90 were necessarily exhibiting symptoms of ALS prior to administration, as SOD1G93A mice exhibit ALS symptoms as of day 30 (as evidenced by Vinsant, 2013b). Azzouz discloses ALS mice treated with EIAV-VEGF at 21 days or 90 days showed increased survival compared to ALS (LacZ) controls (FIG. 2e, 2f) and displayed improved neuromuscular function compare to ALS (LacZ) controls (FIGs. 2a, 2c, 2g, 2h). Azzouz states, “Perhaps the most important observation in our study was that VEGF retained its protective efficacy even when EIAV–VEGF was delivered after half of the motor neurons had died. The therapeutic efficacy of late VEGF delivery is relevant to clinical application in human disease, because ALS occurs sporadically without prior family history and thus cannot be diagnosed before onset in >90% of cases” (page 416).
Kalmar, 2008 administers heat-shock inducer arimoclomol to SOD1G93A mice at day 75 “early-symptomatic stage” or at day 90 “late-symptomatic stage” which correlation with mid- and late- stages of ALS (page 340). Kalmar states, “Disease stages when treatment was initiated were defined by published hallmarks of motor function and spinal cord pathology. Thus, disease onset is defined at around 75 days, when the first signs of weight loss appear (Kieran et al. 2004, 2005). Further pathological symptoms appear at around 90 days when motor deficits occur. Initiation of treatment was set around these dates” (page 340). Thus, administration at day 75 and day 90 is initiated after onset of ALS symptoms in SOD1G93A mice, as defined by Kalmar. Kalmar shows ALS mice treated with armiclomal initiated at day 75 and day 90 showed increased force generation of hindlimb muscles compared to SOD1G93A ALS control mice (page 342, Fig. 1), had greater numbers of surviving motor units, and motor neurons compared to SOD1G93A ALS control mice (pages 343, 345, Fig. 2, Fig. 4), and increased survival compared to SOD1G93A ALS control mice (page 344, Fig. 3).
Kalmar acknowledges the requirement for effective treatments in ALS models after ALS symptom onset stating, “Since most, if not all ALS patients will only present to their clinician after the onset of disease symptoms, it is clear that any approach that is to be of benefit to ALS patients must be effective when given after symptom onset”(page 107); and “Our results, therefore, show that treatment with arimoclomol provides clear benefits in the SODG93A mouse model of ALS mice even when treatment is initiated after symptom onset. These findings may be significant for the clinical development of arimoclomol for the treatment of ALS, since almost all ALS patients only present in the clinic after symptom onset. Indeed, even when the disease is relatively advanced in SODG93A mice, at 90 days, when a very large proportion of motoneurons, around 40%, will already have died” (page 347).
Ikeda, 2015 shows administration of the antioxidant Edaravone to Wobbler mice, a sporatic ALS mouse model, is effective to slows motor neuron degeneration in mice when administered after disease onset in the mice (Abstract). Ikeda discloses administering Edaravone to Wobbler mice when the mice were between 3 to 4 weeks of age, after mice were observed with shaking bodies, which was defined as symptom onset. Ikeda states, “The wobbler mice initially developed shaking body from the age of 3 to 4 weeks, and were diagnosed as the symptomatic onset. Immediately after diagnosis, edaravone or vehicle was administered by intraperitoneal injection daily for 4 weeks” (page 2). Ikeda shows Wobbler mice administered higher doses of Edaravone administered after onset of ALS symptoms showed increased muscle strength and mass compared to Wobbler ALS control mice (Abstract, Fig. 1, 2), and had greater numbers of surviving motor neurons compared to Wobbler ALS control mice (Abstract, Fig. 3).
Thus, the art clearly discloses examples of effective treatments of ALS when treatment is initiated after onset of ALS symptoms – either purposefully by first identifying the disease onset and then initiating treatment, or inherently, wherein treatment is initiated in an ALS animal model at a time point later than the model is known for already exhibiting symptoms of ALS. The Examiner notes that while the above references which rely on Vinsant, 2013b for establishing the mice were treated at a time point after overt symptom onset, because the reference treats mice older than day 30, each reference could equally rely on the disclosure of Mancuso, 2011 or Gerber, 2012, who identified motor deficits in SOD1G93A mice at about 8 weeks or day 60).
Thus, Dr. MacLennan’s statement at paragraph 4 of the Declaration is not persuasive to establish there would be no expectation of success in practicing the claimed invention from the cited prior art of Wang, Davis and Lee, when Wang is evidenced by Vinsant 2013b.
With regard to Applicant’s arguments that none of the cited art show the therapeutic effects seen from the administration of AAV vectors encoding CNTFα shown in the working examples of the specification or those of the Declaration, the Examiner is not persuaded.
The burden is on Applicant to establish the results are unexpected with regard to the claimed invention MPEP716.02(b): “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance;” and the evidence provided must be commensurate with the scope of the claimed invention (MPEP 716.02(d)). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). MPEP 716.02(d).
Independent claim 1 requires administering to a subject already exhibiting (after) onset of ALS symptoms, an AAV encoding CNTFRα, wherein the AAV vector is engineered to increase skeletal muscle expression of CNTFRα, relative to the level of CNTFRα otherwise present in the cell, wherein the method results in the inhibition of motor neuron degeneration. The claim nor specification limit the subject, define the ALS symptom exhibited, identify the type or degree of motor neuron degeneration that is inhibited, and technically, the claim does not require the CNTFRα transgene encoded on the AAV is actually expressed in skeletal muscle (“engineered to increase”). The only functional effect in the claim is that following administration of the AAV-CNTFRα motor neuron degeneration is inhibited.
Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Thus, any specific results seen in specific embodiments of the working examples, such as subject, ALS symptoms, time of administration of the vector after onset of ALS symptom, quantities of administered viral particles, location of administration, etc. do not define the pending claims.
In addition, the working examples of the specification and the Declaration are not commensurate in scope with the pending claims. The claim nor specification limit the subject, define the ALS symptom exhibited, identify the type or degree of motor neuron degeneration that is inhibited, and technically, the claim does not require the CNTFRα transgene encoded on the AAV is actually expressed in skeletal muscle (“engineered to increase”). The only functional effect in the claim is that following administration of the AAV-CNTFRα motor neuron degeneration is inhibited. However, the working examples of the specification and the declaration administer 2 AAV particles, at 2 different dosage concentrations, only at 120-130 days of age, administered in limited locations to a very limited population of mice in total:
Example 3 shows administration of 3 x 1010 vg (n=3) or 6 x 1010 vg (n=8) of an AAV1.1-CNTFRα injected unilaterally into lateral gastrocnemius and soleus muscles of SOD1G93A mice at days 120-130 (paragraphs [0074]-[0075]; FIGs. 2A-2E).
Example 11 shows administration of 3 x 1010 vg (n=3) of an AAV1.1-CNTFRα injected unilaterally into lateral gastrocnemius and soleus muscles of SOD1G93A mice at days 120-130 (paragraph [0094]; FIG. 8). The Examiner notes that it is not clear whether the mice of Example 11 (n=3 receiving 3 x 1010 vg) are in addition to the mice of Example 3 (n = 3 receiving 3 x 1010 vg) – thus demonstrating treatment of a total of n=6 mice receiving 3 x 1010 vg, OR, rather, if the mice of Example 11 are the same mice of Example 3, thus demonstrating treatment of a total of n=3 mice receiving 3 x 1010 vg ,wherein the mice are further analyzed. The specification shows hindlimb injection maintained forelimb motor terminals, indicating a global motor neuron protective effect.
Example 12 shows combined administration of AAV1.1-CNTFRα and AAV1.1-CLC of 3 x 1010 vg of each vector (n=3), 1 x 1010 vg of each vector (n=4), 3 x 109 vg of each vector (n=3) of injected unilaterally into lateral gastrocnemius and soleus muscles of SOD1G93A mice at day 120, “after onset of ALS symptoms” (paragraphs [0099]-[0100]; FIGs. 9A-9B).
At Paragraph 10 of the Declaration, Dr. MacLennan shows administration of 3 x 1010 vg (n=21) of an AAV1.1-CNTFRα injected unilaterally into lateral gastrocnemius and soleus muscles of SOD1G93A mice at day 120.
At Paragraph 12 of the Declaration, Dr. MacLennan carries out additional experiments as those described in Example 11, and shows administration of 3 x 1010 vg (n=5) of an AAV1.1-CNTFRα injected unilaterally into lateral gastrocnemius and soleus muscles of SOD1G93A mice at day 120. The declaration argues the results show hindlimb injection maintained forelimb motor terminals, indicating a global motor neuron protective effect.
At Paragraphs 13-14, Dr. MacLennan analyzes expression of CNTFRα RNA and protein, showing axons/phrenic nerve axon calculations, arguing such results show both local and distal effects of administrated CNTFRα.
At Paragraphs 15-16 of the Declaration, Dr. MacLennan tests two AAV-CNTFRα vectors in TDP-43Q331K mice. Dr. MacLennan administered the AAV1.1-CNTFRα vector (used previously) (n=9) as well as an AAV1-tMCK-skCRM4-CNTFRα vector (n=21) to the TDP-43Q331K mice. “The same AAV treatment procedure was initiated after overt symptom onset (after 3 weeks of declining rotarod performance) to be clinically relevant” (paragraph 15). The data of these experiments is presented in FIG. E of the Declaration. The specific dosages administered in these experiments is presented in the figure text; however, the figure text is illegible, and thus specific dosages are not known.
At Paragraph 17, the declaration states, “Taken together, the data demonstrate that increasing muscle CNTFRα expression with AAV slows ALS progression when initiated after onset of overt symptoms. Prior to our work, as evidenced by the referenced cited in the Office Action, available evidence indicated that ALS could not be treated at that point, more specifically that AAV-directed expression of MN protective neurotrophic factors in muscle could not slow ALS progression after overt symptom onset.”
The Examiner has considered Dr. MacLennan’s statements above, and does not find the evidence or assertions convincing to overcome a prior art rejection over the scope of the pending claims. The prior art need not render obvious the working examples, only the claimed invention. As indicated in the rebuttal above, the claims require administration of an AAV vector encoding CNTFRα administered “after” ALS symptom onset, wherein the method results in the inhibition of motor neuron degeneration. The prior art need not demonstrate the preamble of the claim.
Applicant’s arguments that the art indicated that ALS could not be treated “at that point” improperly attempts to limit the claims to results and embodiments seen from administering the vectors to specific mouse models demonstrating a specific “ALS symptom.” However, the claims are not so limited.
In fact, as noted above, earlier than the time of the invention, the SOD1G93A mice had been reanalyzed for ALS disease onset. Traditional methods used to measure/determine ALS motor deficit were considered insensitive, and asserted as unable to detect subtle motor deficit changes occurring earlier than about day 90/13 weeks (Mancuso, 2011; Vinsant, 2013b; Hayworth, 2009). As a result, additional analysis of ALS symptom onset in SOD1G93A mice using new techniques identified ALS symptoms occur much earlier in life than day 90 (~13 weeks). Mancuso, 2011 identified motor deficit in SOD1G93A mice at about 8 weeks (~ day 56) analyzing paw placement in treadmill locomotion. Gerber, 2012 identified motor deficit at day 60 (~ 8 weeks) analyzing front limb and hind limb placement over a single step in an open field. And, Vinsant, 2013b showed ALS disease symptoms in SOD1G93A mice as early as postnatal days 30 to 40 (~ 4 weeks), exhibited by loss of muscle strength measured by loaded grid test, and variability of gait using an uphill treadmill walking protocol (page 444; FIG 23; FIG 24, Vinsant, 2013b).
To any extent Applicant pointed to sections of the prior art which argues that there is no effective ALS treatment in humans after onset of ALS symptoms, the Examiner notes the present Application and Declaration are likewise deficient, as there is no human data proffered.
With regard to the assertion that administration of the AAV-CNTFRα encoding vector administered in one location was capable of exerting its effect “globally” the claims do not require any particular tissue expression or rescue.
Advancement of prosecution may occur by amending the claims to better reflect the working examples.
112(a) Rejection of Claims 16-17:
The 112(a) rejection over claims 16 and 17 is WITHDRAWN in light of Applicant’s amendments to the claims and/or consideration of Applicant’s arguments dated 5/06/26.
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.
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.
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, of record, as evidenced by Vinsant et al. Characterization of Early Pathogenesis in the SOD1G93A Mouse Model of ALS: Part II, Results and Discussion. Brain and Behavior, 2013. 3(4): 431-457 (Vinsant, 2013b), further in view of US 5,426,177 to Davis of record and Lee, 2013, of record, cited on Applicant’s IDS dated 12/21/22. This is a new rejection necessitated by Applicant’s amendments to the claims.
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). The SOD1G93A mice in Example 4 of Wang were 9 weeks of age when treated with the AAV-GDNF vector (thus, approximately postnatal day 70) (paragraph [0155]). Vinsant, 2013b shows ALS disease symptoms in SOD1G93A mice as early as postnatal day 30, exhibited by loss of muscle strength measured by loaded grid test, and variability of gait using an uphill treadmill walking protocol (page 444; FIG 23; FIG 24, Vinsant, 2013b). Vinsant states, “in the SOD1G93A mouse, symptom onset must be considered to occur at P30, rather than at P70–90 as commonly reported” page 444, and “We propose that P30 therefore represents a more realistic approximation of symptom onset in mutant mice” (page 446). Vinsant, 2013b is cited solely as evidence to show the 9 week old SOD1G93A mice of Wang necessarily exhibited onset of ALS symptoms before they were administered the AAV-GDNF. 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 treated after onset of ALS symptoms 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, as evidenced by Vansant, 2013b, 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 after onset of ALS symptoms, 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 as evidenced by Vinsant, 2013b, 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 in a subject after onset of ALS symptoms, 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, as evidenced by Vinsant, 2013b, 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, of record, as evidenced by Vinsant et al. Characterization of Early Pathogenesis in the SOD1G93A Mouse Model of ALS: Part II, Results and Discussion. Brain and Behavior, 2013. 3(4): 431-457 (Vinsant, 2013b), further in view of US 5,426,177 to Davis of record 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 of record. 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. This is a new rejection necessitated by Applicant’s amendments to the claims.
The disclosures of Wang, as evidenced by Vinsant,2013b, further in view of Davis and Lee are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Wang, as evidenced by Vinsant, 2013b, 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, es evidenced by Vinsant, 2013b, 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, as evidenced by Vinsant, 2013b, 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, as evidenced by Vinsant, 2013b, 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, of record, as evidenced by Vinsant et al. Characterization of Early Pathogenesis in the SOD1G93A Mouse Model of ALS: Part II, Results and Discussion. Brain and Behavior, 2013. 3(4): 431-457 (Vinsant, 2013b, further in view of US 5,4261,77 to Davis of record 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 of record. 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. This is a new rejection necessitated by Applicant’s amendments to the claims.
The disclosures of Wang, as evidenced by Vinsant,2013b, further in view of Davis and Lee are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Wang, as evidenced by Vinsant, 2013b, further in view of Davis and Lee combine to render obvious a method of treating ALS in a subject 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, Vinsant, 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, of record, as evidenced by Vinsant et al. Characterization of Early Pathogenesis in the SOD1G93A Mouse Model of ALS: Part II, Results and Discussion. Brain and Behavior, 2013. 3(4): 431-457 (Vinsant, 2013b) further in view of US 5,426,177 to Davis of record, 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, of record. Claim 19 is directed to an embodiment wherein the AAV vector with enhanced muscle expression comprises a capsid engineered to direct skeletal muscle expression. This is a new rejection necessitated by Applicant’s amendments to the claims.
The disclosures of Wang, as evidenced by Vinsant, 2013b, further in view of Davis and Lee are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Wang as evidenced by Vinsant,2013b, 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, Vinsant 2013, 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, as evidenced by Vinsant, 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, of record, as evidenced by Vinsant et al. Characterization of Early Pathogenesis in the SOD1G93A Mouse Model of ALS: Part II, Results and Discussion. Brain and Behavior, 2013. 3(4): 431-457 (Vinsant, 2013b), further in view of US 5,426,177 to Davis of record, 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, of record. Claim 20 is directed to an embodiment wherein the ALS is characterized by a TDP-43 mutation and/or abnormal TDP-43 distribution. This is a new rejection necessitated by Applicant’s amendments to the claims.
The disclosures of Wang as evidenced by Vinsant 2013b, further in view of Davis and Lee are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Wang, as evidenced by Vinsant 2013, further in view of 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, Vinsant 2013b, 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 in a subject with symptoms of 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, as evidenced by Vinsant 2013b, 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.
Conclusion
No Claims are allowed. No claims are free of the art.
FINAL REJECTION
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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