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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 3, 2026 has been entered.
Detailed Action
This action is in response to the papers filed April 3, 2026.
Amendments
Applicant's amendments, filed April 3, 2026, is acknowledged. Applicant has cancelled Claims 1-14, 16-18, 23-24, 28, and 33, amended Claims 15, 19, 29, and 34.
Claims 15, 19-22, 25-27, 29-32, and 34 are pending and under consideration.
Priority
This application is a 371 of PCT/EP2021/066626 filed on June 18, 2021.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). A certified copy of EPO 20315308.5 filed on June 19, 2020 has been filed with the instant application.
Allowable Subject Matter
1. The following is a statement of reasons for the indication of allowable subject matter:
Claim 22 recites wherein the expression system comprises SEQ ID NO:5 or SEQ ID NO:6.
SEQ ID NO:6 is an AAV vector genome of 3149 nucleotides comprising a 5’ ITR, an expression cassette of SEQ ID NO:5, and a 3’ ITR.
SEQ ID NO:5 is an expression cassette of 2833 nucleotides.
The expression cassette of SEQ ID NO:5 and SEQ ID NO:6 comprises the MCK promoter of SEQ ID NO:4 operably linked to the SGCG coding nucleic acid of SEQ ID NO:3.
SEQ ID NO:5 and SEQ NO:6 are free of the prior art.
Nucleotides 1-1356 of SEQ ID NO:6 are disclosed to encode an rAAV 5’ ITR, the tMCK promoter (SEQ ID NO:4) which comprises a triple tandem MCK enhancer promoter, whereby the triple tandem MCK enhancers and promoter of SEQ ID NO:4 (714 nucleotides) are shown below:
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
CCCTCCCTGGGGACAGCCCCTCCTGGCTAGTCACACCCTGTAGGCTCCTCTATATAACCCAGGGGCACAGGGGCTGCCCCCGGGTCA 714
Rodino-Klapac et al (U.S. Patent 11,358,993; priority to at least April 14, 2017; of record) is considered relevant prior art for having disclosed an rAAV expression vector encoding an MCK promoter operably linked to an alpha-sarcoglycan transgene, whereby the MCK promoter nucleotide sequence (SEQ ID NO:6) comprises a triple tandem MCK enhancer and is 93% identical to instant SEQ ID NO:4, differing from instantly claimed tMCK promoter comprising a triple tandem MCK enhancer nucleotide sequences by seven, dispersed nucleotides, as shown below:
CCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCC
TGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCC
TGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGC
TCGCTCTAAAAATAACCCTGTCCCTGGTGG--CCACTACGGGTCTAGGCTGCCCATGTAA
|||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||
TCGCTCTAAAAATAACCCTGTCCCTGGTGGATCCACTACGGGTCTATGCTGCCCATGTAA
GGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGC
CCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGG
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGG
TCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTG
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTG
G-CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGC
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GACCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGC
CTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGC
||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||
CTGGTTATAATTAACCCCAACACCTGCTG-CCCCCCCCCCCCAACACCTGCTGCCTGAGC
CTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAG
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAG
CTCGCTCTAAAAATAACCCTGTCCCTGGTGGCCCTCCCTGGGGACAGCCCCTCCTGGCTA
||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||
CTCGCTCTAAAAATAACCCTGTCCCTGGT---CCTCCCTGGGGACAGCCCCTCCTGGCTA
GTCACACCCTGTAGGCTCCTCTATATAACCCAGGGGCACAGGGGCTGCCCCCGGGTCAC
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GTCACACCCTGTAGGCTCCTCTATATAACCCAGGGGCACAGGGGCTGCCCCCGGGTCAC
Thus, those of ordinary skill in the art previously recognized the use of a truncated MCK promoter comprising a triple tandem MCK enhancer to drive expression of the artisan’s gene of interest, including a sarcoglycan transgene, in an rAAV expression vector.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
Instant specification fails to disclose an element of criticality for the seven, dispersed nucleotide differences between the prior art truncated MCK promoter comprising a triple tandem MCK enhancer nucleotide sequence and the instantly recited truncated MCK promoter comprising a triple tandem MCK enhancer nucleotide sequence.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
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.
2. The prior rejection of Claims 15, 18-22, 24-27, and 34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to Claim 15 cancelling recitation of the skeletal muscle:heart expression ratio.
3. Claims 29-32 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 15 has been amended to recite a recombinant AAV (rAAV) vector comprising a sequence encoding gamma-sarcoglycan (SGCG) placed under the control of a tMCK promoter having at least 70% identity with SEQ ID NO:4 and allowing expression of SGCG in the skeletal muscles and heart in a human subject.
Claim 29 recites a method of treating a pathology caused by a SGCG deficiency, the method comprising the step of administering to a human subject a pharmaceutical composition comprising the rAAV vector of Claim 15.
While Claim 29 does not recite ipsis verbis “a therapeutically effective amount” or “an effective amount”, it is axiomatic that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), “a therapeutically effective amount” or “an effective amount” of the rAAV of Claim 15 must be administered to the human subject in order to achieve a real-world, clinically meaningful treatment of a pathology caused by a SGCG deficiency, thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A ‘therapeutically effective amount’ and/or ‘an effective amount’ is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the nucleic acid sequence of the promoter [parameter 1];
the type of rAAV viral vector [parameter 2];
the rAAV administration route [parameter 3]; and
the rAAV viral vector dosage administered [parameter 4];
the disease/disorder/condition to be treated [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the rAAV particle that, upon administration to the subject, is not, in fact, ‘a therapeutically effective amount’ and/or ‘an effective amount’ (syn. a sub-therapeutic amount).
Parameter 1
The claims recite a genus of promoters, or variants or derivatives thereof, at a high level of generality.
The specification discloses the % identity to a reference sequence may be as little as 50%, 60%, or 70% (e.g. pg 6, line 25; pg 17, lines 11-12).
70% identity to SEQ ID NO:4 (714 nucleotides) allows for about 215 nucleotide insertions, deletions, and/or substitution, for example.
4^215 = about 3x10^129, 70% identity.
4^143 = about 1x10^86, 80% identity.
(www.calculator.net/exponent-calculator.html; last visited October 29, 2025; of record)
As discussed above, the triple tandem MCK enhancers and promoter of SEQ ID NO:4 (714 nucleotides) are shown below:
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
Thus, the breadth of the claims reasonably encompasses embodiments whereby about 72 nucleotides may be inserted, deleted, and/or substituted (x) within each tMCK enhancer element, for example:
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
The claims reasonably encompass an enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed promoters and/or enhancers that are to have the functional property of yielding transgenic SGCG expression in the skeletal muscle and heart of a human subject.
Parameter 2
The claims are broad for encompassing an enormous genus of at least 125 different AAV capsid serotype variants, including but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV.rh10, and BAAV (DiPrimio et al (U.S. 2009/0215879; Table 3; of record).
Inagaki et al (Robust Systemic Transduction with AAV9 Vectors in Mice: Efficient Global Cardiac Gene Transfer Superior to That of AAV8, Molecular Therapy 14(1): 45-53, 2006; of record) is considered relevant prior art for having taught that both AAV8 and AAV9 are more efficacious to transduce heart muscle, as compared to skeletal muscle (e.g. Figure 3; Table 2A) in mouse subjects. Inagaki et al taught that AAV9 was more efficacious than AAV8 to transduce heart muscle.
Pan et al (AAV-8 Is More Efficient than AAV-9 in Transducing Neonatal Dog Heart, Human Gene Therapy Methods 26: 54-61, 2015; of record) is considered relevant prior art for having taught, Pan et al taught that AAV9 yielded robust skeletal muscle transduction, but little heart transduction (e.g. pg 54, col. 2; pg 56, col. 2, “saturated expression…in skeletal muscle”). Pan et al taught that AAV8 efficiently transduced the right heart, but is barely transduced by AAV9 (e.g. pg 57, col. 1).
Parameter 3
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077] ; of record).
Considering the mode of administration, the specification simply requires administration of the AAV to the subject by any means. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.)
To date, no single mode of gene transfer has provided a viable option for successful gene therapy protocols Daya et al (Gene Therapy Using Adeno-Associated Virus Vectors, Clin. Microbiol. Rev. 21(4): 583-593, 2008; pg 590-591, joining ¶; of record). When considering AAV therapy, there are many obstacles to its use systemically- host cell immune response which leads to toxicity (Daya et al, pg 587, col 2), blood brain as well as cellular barriers against the virus, adequate expression, degradation of the vector or the product.
Fumoto et al (Targeted Gene Delivery: Importance of Administration Routes, INTECH, Novel Gene Therapy Approaches, pg 3-31; editors Wei and Good, publisher Books on Demand, 2013; of record) details these obstacles wherein direct injection is to date the best procedure (pg 11, Table 3, Figure 3, “Direct injection of rAAV vector…exhibited faster and stronger transgene expression than intravenous and intraportal injections”).
Huang et al (Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector, Molecular Therapy 24(6): 1062-1069, 2016; of record) is considered relevant prior art for having taught oral administration of rAAV, whereupon transgene expression was not detected in heart, stomach, intestine, skeletal muscle, kidney, spleen, lung, nor brain (e.g. pg 1062, col. 2; Figure 2).
Tian et al (Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma, Archives of Medical Research 50: 384-392, 2019; of record) is considered relevant art for having taught inhaled administration of rAAV, whereupon AAV vector DNA was detected in the lung, but not detected in other organs, such as heart, liver, kidney, brain, lymph nodes, and gonads (e.g. Abstract; pg 386, col. 2).
Reliance on animal models is not predictive of clinical outcome in humans. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals. Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013; of record) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016; of record) taught that the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
Parameter 4
The claimed methods are recited at a high level of generality for the rAAV vector dosage that is to be administered, including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes, or more (e.g. Vetter et al (U.S. 2023/0103708, [0152]; of record).
Inagaki et al (2006; of record) taught that the relative transduction efficiency of heart and skeletal muscle tissues is a result-effective variable dependent upon the dosage of the AAV8 and AAV9 vectors administered to the mouse subject, whereby very little detectable heart and/or skeletal muscle transduction is detected with a dosage of at least 1x10^10 rAAV vectors. The rAAV dosage for efficient skeletal muscle transduction is not the same as the rAAV dosage for efficient heart muscle transduction (e.g. Figure 3; Table 2A).
Pan et al (2015; of record) taught that a dose of about 1x10^14 AAV8 efficiently transduced the right heart of a canine subject, but is barely transduced by AAV9 (e.g. pg 57, col. 1). Pan et al also taught that cardiac transduction efficiency with AAV9 was a result-effective variable dependent upon the vector dosage, as well as the individual subject (e.g. pg 57, col. 1, “dose-dependent increase”, “[the heart in Barbara] never reached the level seen in Artemis”).
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype (e.g. pg 2, lines 3-15), and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5), as recited in Claim 30.
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses, for example, the therapeutic result includes, but is not limited to:
i) alleviation or amelioration in the severity of a symptom of the disease/disorder (pg 8, line 19; pgs 8-9, joining para);
ii) alleviation or amelioration in the frequency of a symptom of the disease/disorder (pg 8, line 20; pgs 8-9, joining para);
iii) halting progression of the disease/disorder (pg 8, line 21; pgs 8-9, joining para);
iv) curing or eliminating the disease/disorder (pg 8, lines 22-23; pgs 8-9, joining para);
v) preventing or postponing signs of pathology (pg 8, lines 25-29; pgs 8-9, joining para); and
vi) provide a beneficial effect to the subject (pg 8, lines 35-36; pgs 8-9, joining para), which itself is an arbitrary and subjective determination.
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing”. (merriam-webster.com/dictionary/prevent; last visited March 4, 2025)
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to ameliorate a symptom of disease, but not prevent signs of pathology, as opposed to a second rAAV dosage administered via a second administration route, e.g. intravenously, that, while capable of alleviating proximal muscle weakness in the limbs, is unable to cure dilated cardiomyopathy, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. inhalation, that is necessarily and predictably able to ameliorate respiratory insufficency, but not halt progression of DMD-like phenotype(s), as opposed to a second rAAV dosage administered via a second administration route, e.g. transmucosally, that, while capable of reducing the severity of loss of sarcolemma stability, is unable to cure or prevent progressive muscle wasting, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first rAAV dosage administered via a first administration route, e.g. via intrathecal injection, that is unable to reduce, alleviate, and/or ameliorate complications associated with dilated cardiomyopathy, transforms said first rAAV dosage and/or first administration route into one that is now necessarily and predictably capable of curing, preventing, reversing, inhibiting, and/or decreasing dilated cardiomyopathy, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first rAAV dosage administered via a first administration route, e.g. via intraperitoneal injection, that is unable to reduce, alleviate, and/or ameliorate complications associated with Duchenne muscular dystrophy (DMD)-like phenotype, transforms said first rAAV dosage and/or first administration route into one that is now necessarily and predictably capable of curing, preventing, reversing, inhibiting, and/or decreasing Duchenne muscular dystrophy (DMD)-like phenotype, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first rAAV dosage administered via a first administration route, e.g. via intraperitoneal injection, that is unable to reduce, alleviate, and/or ameliorate complications associated with progressive muscle wasting, transforms said first rAAV dosage and/or first administration route into one that is now necessarily and predictably capable of curing, preventing, reversing, inhibiting, and/or decreasing progressive muscle wasting, for example.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, whereby the therapeutically effective amount of the rAAV dosage administered is a result-effective variable dependent upon many different parameters, thereby rendering the claim indefinite.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Applicant asserted secondary consideration was achieved using an AAV8 expression vector comprising the sequence of SEQ ID NO:4 administered intravenously to the rat subject (Figure 8 legend). However, independent Claim 15 is broader in scope than AAV8 vectors and an enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed promoters and/or enhancers that are to have the functional property of yielding transgenic SGCG expression in the skeletal muscle and heart of a human subject.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
4. Claim(s) 15, 20-21, 25-27, 29-32, and 34 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.
Claim 15 has been amended to recite a recombinant AAV (rAAV) vector comprising a sequence encoding gamma-sarcoglycan (SGCG) placed under the control of a tMCK promoter having at least 70% identity with SEQ ID NO:4 and allowing expression of SGCG in the skeletal muscles and heart in a human subject.
Claim 29 recites a method of treating a pathology caused by a SGCG deficiency, the method comprising the step of administering to a human subject a pharmaceutical composition comprising the rAAV vector of Claim 15.
The Examiner incorporates herein the 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection above.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
While Claim 29 does not recite ipsis verbis “a therapeutically effective amount” or “an effective amount”, it is axiomatic that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), “a therapeutically effective amount” or “an effective amount” of the rAAV of Claim 15 must be administered to the human subject in order to achieve a real-world, clinically meaningful treatment of a pathology caused by a SGCG deficiency, thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A ‘therapeutically effective amount’ and/or ‘an effective amount’ is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the nucleic acid sequence of the promoter [parameter 1];
the type of rAAV viral vector [parameter 2];
the rAAV administration route [parameter 3]; and
the rAAV viral vector dosage administered [parameter 4];
the disease/disorder/condition to be treated [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the rAAV particle that, upon administration to the subject, is not, in fact, ‘a therapeutically effective amount’ and/or ‘an effective amount’ (syn. a sub-therapeutic amount).
Parameter 1
The claims recite a genus of promoters, or variants or derivatives thereof, at a high level of generality.
The specification discloses the % identity to a reference sequence may be as little as 50%, 60%, or 70% (e.g. pg 6, line 25; pg 17, lines 11-12).
70% identity to SEQ ID NO:4 (714 nucleotides) allows for about 215 nucleotide insertions, deletions, and/or substitution, for example.
4^215 = about 3x10^129, 70% identity.
4^143 = about 1x10^86, 80% identity.
(www.calculator.net/exponent-calculator.html; last visited October 29, 2025; of record)
As discussed above, the triple tandem MCK enhancers and promoter of SEQ ID NO:4 (714 nucleotides) are shown below:
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTGG
Thus, the breadth of the claims reasonably encompasses embodiments whereby about 72 nucleotides may be inserted, deleted, and/or substituted (x) within each of the three tMCK enhancer elements, for example:
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
The claims reasonably encompass an enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed promoters and/or enhancers that are to have the functional property of yielding transgenic SGCG expression in the skeletal muscle and heart of a human subject.
Blanco et al (Transcription Factor Map Alignment of Promoter Regions, PLoS Computational Biology 2(5): e49, 14 pages, DOI: 10.1371/journal.pcbi.0020049, May, 2006; of record) is considered relevant prior art for having taught that while sequence comparisons and alignments are among the most powerful tools in research in biology, such has limitations because often similar functions are encoded by higher order elements which do not hold a univocal relationship to the underlying primary sequence. In consequence, similar functions are frequently encoded by diverse sequences. Promoter regions, which are functionally defined genetic elements, are a case in point. Often, promoter sequences of genes with similar expression patterns do not show conservation. This is because, even though their expression may be regulated by a similar arrangement of transcription factors, the binding sites for these factors may exhibit great sequence variability (e.g. pg 2, col. 1).
Heinz et al (The selection and function of cell type-specific enhancers, Nat Rev Mol Cell Biol 16, 144–154, doi.org/10.1038/nrm3949, available online February 4, 2015; of record) is considered relevant post-filing art for having taught that enhancers, which are functionally defined genetic elements, may be located at distances ranging from hundreds to millions of nucleotides away from a given target gene (pg 144, col. 1). Beyond the simple annotation of regulatory regions in the genome, it is important to understand how cells select the full complement of enhancers that are required for maintaining their identities and functions. Defining functional enhancer–promoter interactions remains an important goal. Despite being informative, chromatin connectivity maps do not directly relate chromatin interactions to the regulation of gene expres-sion. Definitive evidence that a specific enhancer-like region exerts a transcriptional regulatory function requires the study of mutational effects on that region (e.g. pg 152, col. 2).
Maston et al (Transcriptional Regulatory Elements in the Human Genome, Ann. Rev. Genomics Hum. Genet. 7: 29-59, 2006; of record) is considered relevant prior art for having taught that one of the main emerging challenges for genomics research is to identify all functional elements in the genome, including those that regulate gene expression (pg 30, col. 1). The structure of human gene promoters can be quite complex, typically consisting of multiple transcriptional regulatory elements. The presence of multiple regulatory elements within promoters confers combinatorial control of regulation, which exponentially increases the potential number of unique expression patterns. Such transcriptional regulatory elements include locus control regions (LCRs), insulators, silencers, enhancer, the core promoter, and proximal promoter elements (Figure 1), whereby the distal elements such as LCRs, insulators, silencers, and enhancers may well be over 1 megabase (1 million nucleotides in length) away from the promoter. These regulatory elements can be widely dispersed from the corresponding target gene each regulates (pg 42, col. 2). Identifying the promoter of a specific target gene can be a challenge because the core promoter is often distantly located from the first coding exon (pg 45, col. 1). In addition, because promoters can contain any one of a number of combinations of core promoter elements [and, conversely, many promoters have only one or no such elements (68)], simply searching for the co-occurrence of known core promoter motifs has had only limited success (pg 45, col. 2). Although much improved over earlier prediction programs, these methods still have limited sensitivity and specificity when applied to genome-scale sequence data (pg 45, col. 2). While a number of bioinformatics approaches attempt to list potential transcription factor binding sites based on a statistical match between a region in the sequence and a site matrix. This analysis is often hampered by the prediction of a large number of sites, a significant fraction of which are likely false positives. In addition to the false-positive problem, the completeness of these databases is also an issue; it is likely that not all DNA-binding transcription factors have been identified, and even for some known factors, their binding specificity has not yet been fully characterized. (pg 46, col. 2). Transcription factor binding sites are small and degenerate, are often located distantly from the promoter upon which they act, and are not always conserved through evolution. These properties make regulatory elements difficult to identify through computational means alone (pg 48, col. 2).
Similarly, Thakurta (Computational identification of transcriptional regulatory elements in DNA sequence, Nucleic Acids Res. 34(12): 3585-3598, 2006; of record) is considered relevant prior art for having taught that identification and annotation of all the functional elements in the genome, including genes and the regulatory sequences, is a fundamental challenge in genomics and computational biology. Since regulatory elements are frequently short and variable, their identification and discovery using computational algorithms is difficult (Abstract). However, our knowledge of the transcriptional regulatory elements in the genome and their contribution to gene expression in different spatial and temporal contexts is still limited. Given the complex pattern of regulatory interactions, the challenges involved in the complete elucidation of these elements in the genome are substantial (pg 3593, Conclusion).
The only species disclosed in the rAAV8 or rAAV9 virus whose genome comprises the synthetic tMCK promoter of SEQ ID NO:4 operably linked to the SCGC transgene.
Rodino-Klapac (WO 19/152474; of record in IDS) disclosed an expression system for systemic administration comprising a sequence encoding gamma-sarcoglycan (SGCG) placed under the control of a promoter allowing expression of SGCG in the skeletal muscles and in the heart, e.g. MHCK7 promoter (e.g. Figure 1).
Rodino-Klapac disclosed wherein the promoter is a truncated MCK (tMCK) promoter, wherein the tMCK promoter is at least 60% identical to instant SEQ ID NO:4.
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype (e.g. pg 2, lines 3-15), and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5), as recited in Claim 30.
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses, for example, the therapeutic result includes, but is not limited to:
i) alleviation or amelioration in the severity of a symptom of the disease/disorder (pg 8, line 19; pgs 8-9, joining para);
ii) alleviation or amelioration in the frequency of a symptom of the disease/disorder (pg 8, line 20; pgs 8-9, joining para);
iii) halting progression of the disease/disorder (pg 8, line 21; pgs 8-9, joining para);
iv) curing or eliminating the disease/disorder (pg 8, lines 22-23; pgs 8-9, joining para);
v) preventing or postponing signs of pathology (pg 8, lines 25-29; pgs 8-9, joining para); and
vi) provide a beneficial effect to the subject (pg 8, lines 35-36; pgs 8-9, joining para), which itself is an arbitrary and subjective determination.
The specification does not disclose a definition for “prevents” or “preventing”, and thus is interpreted according to its plain meaning, which is “to keep from happening or existing”. (www.merriam-webster.com/dictionary/prevent; last visited March 4, 2025)
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to ameliorate a symptom of disease, but not prevent signs of pathology, as opposed to a second rAAV dosage administered via a second administration route, e.g. intravenously, that, while capable of alleviating proximal muscle weakness in the limbs, is unable to cure dilated cardiomyopathy, for example.
The claims fail to recite, and the specification fails to disclose, a first rAAV dosage administered via a first administration route, e.g. inhalation, that is necessarily and predictably able to ameliorate respiratory insufficency, but not halt progression of DMD-like phenotype(s), as opposed to a second rAAV dosage administered via a second administration route, e.g. transmucosally, that, while capable of reducing the severity of loss of sarcolemma stability, is unable to cure or prevent progressive muscle wasting, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first rAAV dosage administered via a first administration route, e.g. via intrathecal injection, that is unable to reduce, alleviate, and/or ameliorate complications associated with dilated cardiomyopathy, transforms said first rAAV dosage and/or first administration route into one that is now necessarily and predictably capable of curing, preventing, reversing, inhibiting, and/or decreasing dilated cardiomyopathy, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first rAAV dosage administered via a first administration route, e.g. via intraperitoneal injection, that is unable to reduce, alleviate, and/or ameliorate complications associated with Duchenne muscular dystrophy (DMD)-like phenotype, transforms said first rAAV dosage and/or first administration route into one that is now necessarily and predictably capable of curing, preventing, reversing, inhibiting, and/or decreasing Duchenne muscular dystrophy (DMD)-like phenotype, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first rAAV dosage administered via a first administration route, e.g. via intraperitoneal injection, that is unable to reduce, alleviate, and/or ameliorate complications associated with progressive muscle wasting, transforms said first rAAV dosage and/or first administration route into one that is now necessarily and predictably capable of curing, preventing, reversing, inhibiting, and/or decreasing progressive muscle wasting, for example.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, whereby the therapeutically effective amount of the rAAV dosage administered is a result-effective variable dependent upon many different parameters, thereby rendering the claim indefinite.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Applicant asserted secondary consideration was achieved using an AAV8 expression vector comprising the sequence of SEQ ID NO:4 administered intravenously to the rat subject (Figure 8 legend). However, independent Claim 15 is broader in scope than AAV8 vectors and an enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed promoters and/or enhancers that are to have the functional property of yielding transgenic SGCG expression in the skeletal muscle and heart of a human subject.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial rAAV expression vector is to comprise a tMCK promoter having the sequence of SEQ ID NO:4 operably linked to the SGCG transgene does not tell you anything at all about:
i) the enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed variants of SEQ ID NO:4 that will necessarily and predictably have the functional properties of expressing the SGCG transgene in the skeletal muscles and/or heart of a human subject [parameter 1];
ii) the broad genus of rAAV vector serotypes [parameter 2];
iii) the broad genus of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration [parameter 3];
iv) the enormously broad genus of unrecited and undisclosed rAAV vector dosages that is/are to be administered to the human subject [parameter 4];
v) an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5]; and/or
vi) an enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure a pathology caused by a SGCG deficiency in a human subject.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
i) an enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed variants of SEQ ID NO:4 that will necessarily and predictably have the functional properties of expressing the SGCG transgene in the skeletal muscles and/or heart of a human subject [parameter 1];
ii) a broad genus of rAAV vector serotypes [parameter 2];
iii) a broad genus of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration [parameter 3];
iv) an enormously broad genus of unrecited and undisclosed rAAV vector dosages that is/are to be administered to the human subject [parameter 4];
v) an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5]; and/or
vi) an enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6].
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
i) the enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed variants of SEQ ID NO:4 that will necessarily and predictably have the functional properties of expressing the SGCG transgene in the skeletal muscles and/or heart of a human subject [parameter 1];
ii) the broad genus of rAAV vector serotypes [parameter 2];
iii) the broad genus of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration [parameter 3];
iv) the enormously broad genus of unrecited and undisclosed rAAV vector dosages that is/are to be administered to the human subject [parameter 4];
v) an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5]; and/or
vi) an enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure a pathology caused by a SGCG deficiency in a human subject, at the time the application was filed.
At best, the only species disclosed is the rAAV8 or rAAV9 virus whose genome comprises the tMCK promoter of SEQ ID NO:4 operably linked to the SCGC transgene.
At best, the only species disclosed is the rAAV8 or rAAV9 virus whose genome comprises the tMCK promoter of SEQ ID NO:4 operably linked to the SCGC transgene, whereby said rAAV8 or rAAV9 is administered intravenously to a rodent—not human—subject at a dose of at least 5x10^12 vector genomes/kg.
While the specification discloses transgene expression, the specification is silent to achieving the enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure a pathology caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5] in a mouse, rat, macaca, and/or human subject.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
Response to Arguments
Applicant argues that there is a well-established structure-function relationship in the art between promoters and gene expression, and the specification describes promoters that drive SGCG expression in skeletal muscle and the heart.
Applicant’s argument(s) has been fully considered, but is not persuasive. The claims reasonably encompass an enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed promoters and/or enhancers that are to have the functional property of yielding transgenic SGCG expression in the skeletal muscle and heart of a human subject.
The breadth of the claims reasonably encompasses embodiments whereby about 72 nucleotides may be inserted, deleted, and/or substituted (x) within each of the three tMCK enhancer elements, for example:
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
At best, the only species disclosed is the rAAV8 or rAAV9 virus whose genome comprises the tMCK promoter of SEQ ID NO:4 operably linked to the SCGC transgene.
5. Claims 15, 20-21, 25-27, 29-32, and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for rAAV8 or rAAV9 virus whose genome comprises a chimeric MCK promoter/triple tandem MCK enhancer (tMCK) comprising the nucleotide sequence of SEQ ID NO:4 operably linked to the SCGC transgene,
does not reasonably provide enablement for i) the enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed variants of SEQ ID NO:4 that will necessarily and predictably have the functional properties of expressing the SGCG transgene in the skeletal muscles and/or heart of a human subject [parameter 1];
ii) the broad genus of rAAV vector serotypes [parameter 2];
iii) the broad genus of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration [parameter 3];
iv) the enormously broad genus of unrecited and undisclosed rAAV vector dosages that is/are to be administered to the human subject [parameter 4];
v) an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5]; and/or
vi) an enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure a pathology caused by a SGCG deficiency in a human subject.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial rAAV expression vector is to comprise a tMCK promoter having the sequence of SEQ ID NO:4 operably linked to the SGCG transgene does not tell you anything at all about:
i) the enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed variants of SEQ ID NO:4 that will necessarily and predictably have the functional properties of expressing the SGCG transgene in the skeletal muscles and/or heart of a human subject [parameter 1];
ii) the broad genus of rAAV vector serotypes [parameter 2];
iii) the broad genus of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration [parameter 3];
iv) the enormously broad genus of unrecited and undisclosed rAAV vector dosages that is/are to be administered to the human subject [parameter 4];
v) an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5]; and/or
vi) an enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure a pathology caused by a SGCG deficiency in a human subject.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
i) an enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed variants of SEQ ID NO:4 that will necessarily and predictably have the functional properties of expressing the SGCG transgene in the skeletal muscles and/or heart of a human subject [parameter 1];
ii) a broad genus of rAAV vector serotypes [parameter 2];
iii) a broad genus of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration [parameter 3];
iv) an enormously broad genus of unrecited and undisclosed rAAV vector dosages that is/are to be administered to the human subject [parameter 4];
v) an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5]; and/or
vi) an enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6].
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
i) the enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed variants of SEQ ID NO:4 that will necessarily and predictably have the functional properties of expressing the SGCG transgene in the skeletal muscles and/or heart of a human subject [parameter 1];
ii) the broad genus of rAAV vector serotypes [parameter 2];
iii) the broad genus of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration [parameter 3];
iv) the enormously broad genus of unrecited and undisclosed rAAV vector dosages that is/are to be administered to the human subject [parameter 4];
v) an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5]; and/or
vi) an enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure a pathology caused by a SGCG deficiency in a human subject, at the time the application was filed.
At best, the only species disclosed is the rAAV8 or rAAV9 virus whose genome comprises the tMCK promoter of SEQ ID NO:4 operably linked to the SCGC transgene.
At best, the only species disclosed is the rAAV8 or rAAV9 virus whose genome comprises the tMCK promoter of SEQ ID NO:4 operably linked to the SCGC transgene, whereby said rAAV8 or rAAV9 is administered intravenously to a rodent—not human—subject at a dose of at least 5x10^12 vector genomes/kg.
While the specification discloses transgene expression, the specification is silent to achieving the enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure a pathology caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5] in a mouse, rat, macaca, and/or human subject.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to formulate and administer:
i) the enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed variants of SEQ ID NO:4 that will necessarily and predictably have the functional properties of expressing the SGCG transgene in the skeletal muscles and/or heart of a human subject [parameter 1];
ii) the broad genus of rAAV vector serotypes [parameter 2];
iii) the broad genus of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic administration [parameter 3];
iv) the enormously broad genus of unrecited and undisclosed rAAV vector dosages that is/are to be administered to the human subject [parameter 4];
v) an enormous genus of pathologically distinct disorders caused by a SGCG deficiency, including, but not limited to, loss of stability in the sarcolemma, loss of protection of muscle fibers from contraction-induced damage, progressive muscle wasting, proximal muscle weakness in the limbs, common calf hypertrophy, early joint contractures, respiratory insufficiency, dilated cardiomyopathy, severe Duchenne muscular dystrophy (DMD)-like phenotype, and Limb-Girdle Muscular Dystrophy type C (LGMD2C or LGMDR5) [parameter 5]; and/or
vi) an enormous genus of physiologically and phenotypically different results, including, but is not limited to alleviation or amelioration in the severity of a symptom of the disease/disorder, alleviation or amelioration in the frequency of a symptom of the disease/disorder, halting progression of the disease/disorder, curing or eliminating the disease/disorder, preventing or postponing signs of pathology; and providing a beneficial effect to the subject [parameter 6], so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result to treat, prevent, and/or cure a pathology caused by a SGCG deficiency in a human subject.
The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy. At issue in general are organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, the nucleic acid is broadly stated as being administered to a patient. The lack of guidance exacerbates the highly unpredictable field of gene therapy and the method of delivery of polynucleotides is highly unpredictable to date. Gene delivery has been a persistent problem for gene therapy protocols and the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically.
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
As discussed above, Mingozzi and High (2013; of record) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
As discussed above, Kattenhorn et al (November 28, 2016; of record) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for enablement under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
Claim Rejections - 35 USC § 102
6. The prior rejections of Claim(s) 15, 20, 24-25, 27, and 29-32 under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2) as being by Rodino-Klapac (WO 19/152474; of record in IDS) are withdrawn in light of Applicant’s amendment to the independent claim to recite at least 70% identity to SEQ ID NO:4. Rodino-Klapac (WO 19/152474) disclosed wherein the tMCK promoter is at least 60% identical to instant SEQ ID NO:4.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
7. The prior rejection of Claim 21 under AIA 35 U.S.C. 103 as being unpatentable over Rodino-Klapac (WO 19/152474; of record in IDS/Search Report) is withdrawn for reasons discussed above.
8. The prior rejection of Claims 23-26 under AIA 35 U.S.C. 103 as being unpatentable over Rodino-Klapac (WO 19/152474; of record in IDS/Search Report), as applied to Claims 15, 20, 24-25, and 27 above, and in further view of Israeli et al (An AAV-SGCG Dose-Response Study in a gamma-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress, Molecular Therapy: Methods & Clinical Development 13: 494-502; available online May 9, 2019; of record in IDS) is withdrawn for reasons discussed above.
9. The prior rejection of Claims 18, 24-25, 27, and 34 under AIA 35 U.S.C. 103 as being unpatentable over Rodino-Klapac (WO 19/152474; of record in IDS/Search Report), as applied to Claims 15, 20, 24-25, and 27 above, and in further view of Rodino-Klapac et al (U.S. 2019/0202880; published July 4, 2019; filed October 11, 2018) is withdrawn for reasons discussed above.
10. Claim(s) 15, 19-21, 25, 27, and 34 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Rodino-Klapac (WO 19/152474; of record in IDS/Search Report; hereafter RK-1) in view of Rodino-Klapac et al (WO 17/180976; hereafter RK-2).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 15, 19, and 34, RK-1 is considered relevant prior art for having disclosed a recombinant AAV viral vector expression vector comprising a sequence encoding gamma-sarcoglycan (SGCG) placed under the control of a promoter allowing expression of SGCG in the skeletal muscles and in the heart, e.g. MHCK7 promoter (e.g. Figure 1), wherein the promoter is a truncated MCK (tMCK) promoter, wherein the tMCK promoter is at least 60% identical to instant SEQ ID NO:4.
RK-1 do not disclose wherein the tMCK promoter is at least 60% identical to instant SEQ ID NO:4.
However, prior to the effective filing date of the instantly claimed invention, RK-2 is considered relevant prior art for having disclosed a recombinant AAV vector whose genome comprises an MCK promoter operably linked to an alpha-sarcoglycan transgene, whereby the MCK promoter nucleotide sequence ([0019]; SEQ ID NO:6) comprises a triple tandem MCK enhancer and is 93% identical to instant SEQ ID NO:4, differing from instantly claimed tMCK promoter comprising a triple tandem MCK enhancer nucleotide sequences by seven, dispersed nucleotides, as shown below:
CCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CCCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGCC
TGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGCC
TGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAGC
TCGCTCTAAAAATAACCCTGTCCCTGGTGG--CCACTACGGGTCTAGGCTGCCCATGTAA
|||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||
TCGCTCTAAAAATAACCCTGTCCCTGGTGGATCCACTACGGGTCTATGCTGCCCATGTAA
GGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGC
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GGAGGCAAGGCCTGGGGACACCCGAGATGCCTGGTTATAATTAACCCCAACACCTGCTGC
CCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGG
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CCCCCCCCCCCCAACACCTGCTGCCTGAGCCTGAGCGGTTACCCCACCCCGGTGCCTGGG
TCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTG
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TCTTAGGCTCTGTACACCATGGAGGAGAAGCTCGCTCTAAAAATAACCCTGTCCCTGGTG
G-CCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGC
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GACCACTACGGGTCTAGGCTGCCCATGTAAGGAGGCAAGGCCTGGGGACACCCGAGATGC
CTGGTTATAATTAACCCCAACACCTGCTGCCCCCCCCCCCCCAACACCTGCTGCCTGAGC
||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||
CTGGTTATAATTAACCCCAACACCTGCTG-CCCCCCCCCCCCAACACCTGCTGCCTGAGC
CTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAG
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CTGAGCGGTTACCCCACCCCGGTGCCTGGGTCTTAGGCTCTGTACACCATGGAGGAGAAG
CTCGCTCTAAAAATAACCCTGTCCCTGGTGGCCCTCCCTGGGGACAGCCCCTCCTGGCTA
||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||
CTCGCTCTAAAAATAACCCTGTCCCTGGT---CCTCCCTGGGGACAGCCCCTCCTGGCTA
GTCACACCCTGTAGGCTCCTCTATATAACCCAGGGGCACAGGGGCTGCCCCCGGGTCAC
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GTCACACCCTGTAGGCTCCTCTATATAACCCAGGGGCACAGGGGCTGCCCCCGGGTCAC
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
The instantly recited tMCK promoter nucleic acid SEQ ID NO:4 differs by just seven, dispersed nucleotides of RK-1.
Instant specification fails to disclose an element of criticality for the seven, dispersed nucleotide differences.
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology and the design and synthesis of gene expression vectors. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first tMCK promoter having about 60% identity to instant SEQ ID NO:4, as disclosed by RK-1, with a second tMCK promoter having about 93% identity to instant SEQ ID NO:4, as disclosed by RK-2, in a rAAV expression vector to express a sarcoglycan transgene of interest, including gamma-sarcoglycan, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first tMCK promoter having about 60% identity to instant SEQ ID NO:4, as disclosed by RK-1, with a second tMCK promoter having about 93% identity to instant SEQ ID NO:4, as disclosed by RK-2, in a rAAV expression vector to express a sarcoglycan transgene of interest, including gamma-sarcoglycan, because RK-2 successfully demonstrated the ability of the tMCK promoter having about 93% identity to instant SEQ ID NO:4 to direct expression of beta-sarcoglycan in skeletal muscles (e.g. [0039], “expression of the…sarcoglycan transgene at levels averaging 80%”).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
With respect to Claim 20, RK-1 disclosed wherein the SGCG protein (lower line) has the amino acid sequence of SEQ ID NO: 2 (upper line), as shown below:
MVREQYTTATEGICIERPENQYVYKIGIYGWRKRCLYLFVLLLLIILVVNLALTIWILKV 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MVREQYTTATEGICIERPENQYVYKIGIYGWRKRCLYLFVLLLLIILVVNLALTIWILKV 60
MWFSPAGMGHLCVTKDGLRLEGESEFLFPLYAKEIHSRVDSSLLLQSTQNVTVNARNSEG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MWFSPAGMGHLCVTKDGLRLEGESEFLFPLYAKEIHSRVDSSLLLQSTQNVTVNARNSEG 120
EVTGRLKVGPKMVEVQNQQFQINSNDGKPLFTVDEKEVVVGTDKLRVTGPEGALFEHSVE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EVTGRLKVGPKMVEVQNQQFQINSNDGKPLFTVDEKEVVVGTDKLRVTGPEGALFEHSVE 180
TPLVRADPFQDLRLESPTRSLSMDAPRGVHIQAHAGKIEALSQMDILFHSSDGMLVLDAE 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TPLVRADPFQDLRLESPTRSLSMDAPRGVHIQAHAGKIEALSQMDILFHSSDGMLVLDAE 240
TVCLPKLVQGTWGPSGSSQSLYEICVCPDGKLYLSVAGVSTTCQEHNHICL 291
|||||||||||||||||||||||||||||||||||||||||||||||||||
TVCLPKLVQGTWGPSGSSQSLYEICVCPDGKLYLSVAGVSTTCQEHNHICL 291
With respect to Claim 21, RK-1 disclosed wherein the nucleic acid sequence (SEQ ID NO:9) (lower line) encoding the SGCG amino acid sequence of SEQ ID NO:2 comprises a nucleotide sequence that is 99.8% identical (2 mismatches) to instant SEQ ID NO:3 (upper line), whereby one of the two mismatches is the terminal stop codon, as shown below:
CTTTCTCAAATGGATATTCTTTTTCATAGTAGTGATGGAATGCTCGTGCTTGATGCTGAA 720
|||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||
CTTTCTCAAATGGATATTCTTTTTCATAGTAGTGATGGAATGCTTGTGCTTGATGCTGAA 720
ACCACGTGCCAGGAGCACAGCCACATCTGCCTCTAA 876
|||||||||||||||||||||||||||||||||| |
ACCACGTGCCAGGAGCACAGCCACATCTGCCTCTGA 876
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
The instantly recited nucleic acid and the prior art nucleic acid differ by just one coding nucleotide, and encode the identical amino acid sequence.
Instant specification fails to disclose an element of criticality for the single nucleotide difference.
With respect to Claim 25, RK-1 disclosed wherein the AAV vector is of serotype 8 or 9 (e.g. [0015]).
RK-2 disclosed wherein the AAV vector is of serotype 8 or 9 (e.g. [0020]).
With respect to Claim 27, RK-1 disclosed a pharmaceutical composition comprising the expression system (e.g. [00111]).
RK-2 disclosed a pharmaceutical composition comprising the expression system (e.g. [0069]).
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that RK-2 experimentally used the MHCK7 promoter, as distinguished from the tMCK promoter, to augment cardiac expression.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, RK-2 successfully demonstrated the ability of the tMCK promoter having about 93% identity to instant SEQ ID NO:4 to direct expression of beta-sarcoglycan in skeletal muscles (e.g. [0039], “expression of the…sarcoglycan transgene at levels averaging 80%”).
As a second matter, instant claims are directed to an rAAV product, not a method of use.
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The phrase “drives expression of SGCG in the skeletal muscles and in the heart of the [human] subject” is an intended use limitation, which does not contain any further structural limitations with respect to claimed tMCK promoter having at least 70% identity to instant SEQ ID NO:4 (see MPEP §2114).
Since the Patent Office does not have the facilities for examining and comparing Applicant’s genus of tMCK promoters having at least 70% identity to instant SEQ ID NO:4 with the RK-2 tMCK promoter having about 93% identity to instant SEQ ID NO:4, the burden is upon applicants to show a distinction between the material structural and functional characteristics of the claimed tMCK promoters having at least 70% identity to instant SEQ ID NO:4 and the RK-2 tMCK promoter having about 93% identity to instant SEQ ID NO:4. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
Applicant provides no objective evidence that the RK-2 tMCK promoter having about 93% identity to instant SEQ ID NO:4 is unable to drive expression in the heart of a human subject.
The claims reasonably encompass an enormously vast genus of about 3x10^129, and/or 1x10^86 structurally and functionally undisclosed promoters and/or enhancers that are to have the functional property of yielding transgenic SGCG expression in the skeletal muscle and heart of a human subject.
The breadth of the claims reasonably encompasses embodiments whereby about 72 nucleotides may be inserted, deleted, and/or substituted (x) within each of the three tMCK enhancer elements, for example:
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
CxACxAxGxxTCxAxGCxGCxCAxGxAAxGAxGxAAxGCxTxGxGxxAxCCGAGxTGxCTxGTTAxAAxTAAxCCxAACAxCTGCTGCCxCxxCCCCxxCAxCACCxGCTxCCTGAxCCTGAxxGGxTACxxCAxxCxxGTGCxxGxGTxxTAGxxTCTxxACACxxTGxxGGAGAxxCTCxCTCTxxAAATAxCCxxGTCxxTGxxGG
At best, the only species disclosed is the rAAV8 or rAAV9 virus whose genome comprises the tMCK promoter of SEQ ID NO:4 operably linked to the SCGC transgene.
See also the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description and enablement rejections, and the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Applicant argues that the Examiner has exercised impermissible hindsight.
Applicant’s argument(s) has been fully considered, but is not persuasive. 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).
Applicant does not contest conclusion of obviousness for a nucleotide sequence encoding a SGCG protein having the amino acid sequence of SEQ ID NO: 2.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
The instantly recited nucleic acid and the prior art nucleic acid differ by just one coding nucleotide, and encode the identical amino acid sequence.
Instant specification fails to disclose an element of criticality for the single nucleotide difference.
11. Claims 25-27 are rejected under AIA 35 U.S.C. 103 as being unpatentable over RK-1 in view of RK-2, as applied to Claims 15, 19-21, 25, 27, and 34 above, and in further view of Israeli et al (available online May 9, 2019; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
As discussed above, RK-1 and RK-2 disclosed wherein the expression
system comprises a viral vector, including an rAAV vector, wherein the AAV vector is of serotype 8 or 9.
RK-1 and RK-2 do not disclose a specific example wherein the AAV virus is AAV2/8 or AAV2/9.
However, prior to the effective filing date of the instantly claimed invention, Israeli et al is considered relevant prior art for having taught an rAAV2/8 virus whose genome comprises a SGCG transgene operably linked to a muscle-specific promoter (e.g. Abstract; Figure 1a).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first rAAV8 encoding an SGCG transgene, as disclosed by Rodino-Klapac, with a second rAAV8 encoding an SGCG transgene, i.e. an rAAV2/8, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first rAAV8 encoding an SGCG transgene with a second rAAV8 encoding an SGCG transgene, i.e. an rAAV2/8, because those of ordinary skill in the art had long-recognized the AAV vector backbone of AAV2 was routinely used in the art, which can then be packaged using AAV8 capsid proteins, as successfully demonstrated by Israeli et al (e.g. pg 500, col. 2), whereby Israeli et al taught that the rAAV2/8 virus was recognized to have better transduction efficiency of striated muscles, as compared to AAV1 (e.g. pg 498, col. 1) and was able to transduce nearly 100% of the skeletal muscle myofibers upon intramuscular injection (e.g. pg 495, col. 1).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 27, RK-1 and RK-2 disclosed a pharmaceutical composition comprising the expression system.
Israeli et al taught a pharmaceutical composition comprising the expression system (e.g. pg 500, col. 2).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Israeli et al do not cure the defect of Rodino-Klapac.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner’s response to Applicant's argument(s) regarding Rodino-Klapac are discussed in prior Office Actions, and incorporated herein.
Applicant does not contest the teachings of Israeli et al as applied to the obviousness to substitute a first rAAV8 encoding an SGCG transgene, as disclosed by Rodino-Klapac, with a second rAAV8 encoding an SGCG transgene, i.e. an rAAV2/8, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first rAAV8 encoding an SGCG transgene with a second rAAV8 encoding an SGCG transgene, i.e. an rAAV2/8, because those of ordinary skill in the art had long-recognized the AAV vector backbone of AAV2 was routinely used in the art, which can then be packaged using AAV8 capsid proteins, as successfully demonstrated by Israeli et al (e.g. pg 500, col. 2), whereby Israeli et al taught that the rAAV2/8 virus was recognized to have better transduction efficiency of striated muscles, as compared to AAV1 (e.g. pg 498, col. 1) and was able to transduce nearly 100% of the skeletal muscle myofibers upon intramuscular injection (e.g. pg 495, col. 1).
Conclusion
12. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights