DETAILED ACTION
Claims 2-47 were/stand cancelled. Claim 1 was amended. Claims 1 and 48-61 are pending.
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 .
Priority
This application is a 371 of PCT/GB2021/052197 (08/24/2021) which claims priority to UNITED KINGDOM 2013194.2 (08/24/2020) as reflected in the filing receipt issued July 12 2023.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 21 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 48 is objected to because of the following informalities: the abbreviation AAV should be spelt out the first time it occurs. For the purposes of examination, the term “AAV” is interpreted to mean adeno-associated virus. Appropriate correction is required.
Claim 52 is objected to because of the following informalities: the abbreviation CRM8 and HCR should be spelt out the first time it occurs. For the purposes of examination, the term “CRM8” is interpreted to mean cis-acting regulatory module and “HCR” is interpreted to mean hepatic control region. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 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 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.
Claim 61 is rejected under 35 U.S.C. 103 as being unpatentable over Jia et al. (Mol. Biol. Rep., 2010) in view of Lewis et al. (Redox Biology, 2020, available online January 11 2020) as evidenced by Cassard et al. (J Cell Biochem) and NM_021833.5.
Applicant Claims
The instant application claims a nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 12, or a nucleotide sequence with at least 75% identity thereto.
The instant specification teaches that this sequence is a codon optimized UCP1 (see page 4).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Jia et al. is directed to the polymorphisms of UCP1 genes associated with fat metabolism, obesity and diabetes. The human UCP-1 gene has been located on a long arm of chromosome 4 and the first genetic polymorphisms of UCP1 which were found to be an A-G point mutation. It is taught that uncoupling protein 1 was identified in BAT (brown adipose tissue) and has since been found to reside in the inner mitochondrial membrane in BAT. Jia et al. refers to Cassard-Doulcier for the structure of UCP1 (see reference 9) (page 1514).
As shown below instantly claimed SEQ ID NO: 12 has 73% identity to human UCP1 wherein the sequence was obtained from Cassard-Doulcier et al.:
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Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Jia et al. teaches the UCP1 is found in mitochondria and that polymorphisms in the gene exists, Jia et al. does not teach a sequence with at least 75% identity to instant SEQ ID No: 12. However, this deficiency is cured by Lewis et al.
Lewis et al. is directed to codon optimization which is an essential parameter for the efficient allotopic expression of mtDNA genes. It is taught that mutations in mitochondrial DNA can be inherited or occur de novo leading to several debilitating myopathies with no curative option and few or no effective treatments (abstract). The prospect of targeted mitochondrial therapies is of great clinical interest (page 1). Fig. 1 shows amino acid composition and codon use including codon optimized mitochondrial genes. Many commercial algorithms have therefore been developed to determine the optimal sequence and conditions for expression of a gene from a particular host. Though there are concerns regarding the use of codon optimization to increase homologous expression of a nuclear gene, such as the generation of novel or immunogenic peptides or structural perturbations in the encoded protein, clinical gene therapy using a codon-optimized exogenous construct to compensate for mutations in a nuclear gene is ongoing, and codon optimization continues to be widely utilized for the production of biotherapeutics (page 2). It is taught that codon-optimization of mitochondrial genes enhances transient expression in mammalian cells (section 2.1). It was found that in every case, transcripts for the codon-optimized gene was substantially higher than its minimally recoded counterpart (page 3, right column).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Liu et al. and Lewis et al. and form a codon-optimized nucleic acid of UCP1. One skilled in the art would have been motivated to perform codon-optimization as it has been shown to enhance transient expression of mitochondrial genes in mammalian cells as taught by Lewis et al. Since UCP1 is found in the mitochondria that is associated with fat metabolism, obesity and diabetes, one skilled in the art would have been motivated top codon optimize the UCP1 gene in order to use for gene therapy.
Since SEQ ID NO: 12 is already 73% identical to UCP1, the expectation would be that codon optimization of UCP1 would produce a nucleic acid which is at least 75% identity to SEQ ID NO: 12.
Claims 1, 48-52, 54 and 56-60 are rejected under 35 U.S.C. 103 as being unpatentable over Ishigaki et al. (Diabetes, 2005) in view of GenBank (U28480.1, 1996), Zadeh et al. (J Hepatol, 2013) and Smith et al. (USPGPUB No. 20170290926).
Applicant Claims
The instant application claims a method for inhibiting a lipodystrophy in a subject comprising administering a vector comprising a promoter operably linked to a nucleic acid encoding mitochondrial uncoupling protein 1 (UCP1) to a subject having lipodystrophy wherein the promoter is a liver specific protomer, the nucleic acid encoding UCP encodes a functional human UCP1 protein having SEQ ID NO: 2 or at least 90% sequence identity thereto and an intron is included in the nucleic acid encoding UCP1 or before the UPC1 gene.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Ishigaki et al. is directed to dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated with obesity. Uncoupling proteins were discovered members of the mitochondrial inner membrane carrier family. UCP1 (thermogenin) plants an important role in mediating cold exposure-induced thermogenesis and is also a likely regulator of diet-induced thermogenesis. Overexpression of UCPs in white adipose tissue and skeletal muscle has preventive effects on development of genetic and dietary obesity the resultant insulin resistance (page 322). The liver is one of the major metabolic organs involved in glucose and lipid metabolism and insulin action. The liver can store and release abundant fat. Taught is expression of UCP1 protein in the liver, before or after diabetes associated with dietary obesity had developed. It was found that hepatic UCP1 expression improved diabetes and obesity under high-fat diet conditions (pages 322-323 bridging paragraph). Shown in figure 1 hepatitic UCP1 expression reduced body weight and blood glucose levels. Enhancement of UCPs in the liver is a potential therapy for the metabolic syndrome via reductions in adiposity and blood glucose levels as well as possible reactive oxygen species in obese and diabetic individuals (page 331). Taught is the UCP1 adenovirus vector was administered intravenously (page 324, results).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Ishigaki et al. teaches UCP1, Ishigaki et al. does not expressly teach UCP1 with a sequence of SEQ ID NO: 2 but that deficiency is cured by GenBank.
While Ishigaki et al. teaches administering a vector with UCP1, Ishigaki et al. does not expressly teach the subject has lipodystrophy or the promoter is liver specific or an intron is required to be present in the vector. However, these deficiencies are cured by Zadeh et al. and
Zadeh et al. is directed to the liver diseases of lipodystrophy. The lipodystrophies are a group of syndromes in which the cardinal clinical feature is partial
or complete absence of adipose tissue. As a group they are characterized by severe
insulin resistance, severe hypertriglyceridemia, low HDL cholesterol, low leptin and
adiponectin, ectopic fat accumulation, non-alcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). NAFLD is a chronic liver disorder frequently found in conjunction with obesity and the metabolic syndrome, and is increasingly recognized in patients with abnormal liver tests found on routine screening. Thus, lipodystrophy represents an extreme version of the common, obesity-associated
“Metabolic Syndrome” (page 2, introduction). Patients can have familiar partial lipodystrophy (FPL) and NAFLD (figure 3).
Smith et al. is directed to adeno-associated viral vectors for the gene therapy of metabolic diseases. Smith et al. teaches that the current epidemic of obesity and the metabolic syndrome is a global health problem. Adipose tissue has a vital role in regulating energy homeostasis, and the interest in the complex biology of adipose tissue is increasing greatly (paragraph 0002). Claimed is a method of treatment and/or prevention of a disease wherein an adeno-associated viral vector is administered (claim 77). The disease is selected from the group consisting of obesity, insulin resistance, type 2 diabetes, liver cirrhosis and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) (claim 78). Taught is an adeno-associated viral (AAV) vector comprising a recombinant viral genome which comprises an expression cassette comprising a transcriptional regulatory region linked to a nucleotide sequence encoding BMP4 wherein the cassette comprises a promoter and enhancer (paragraph 0037). AAV vectors taught include AAV3 and AAV8 (paragraph 0041). The polynucleotide is under the control of a liver-specific promoter which refers to a nucleic acid sequence that serves as a promoter (i.e. regulates expression of a selected nucleic acid sequence operably linked to the promoter) and which affects the expression of a selected nucleic acid sequence in specific tissues cells, such as hepatocytes. A liver specific promoter is more active in liver and include an alpha1-anti-trypsin (AAT) promoter, a thyroxin-binding globulin (TBG) promoter, an HCR-hAAT hybrid promoter, a transthyretin promoter (aka TTR), etc. (paragraph 0053). An enhancer is a DNA sequence element to which transcription factors bind to increase gene transcription. Enhancers include an HCR enhancer which is preferred because it is liver-specific as HCR is a hepatic control region enhancer (paragraph 0056). In a preferred embodiment, the liver-specific transcriptional-regulatory region of the AAV vector according to the invention comprises the liver-specific enhancer HCR (hepatic control region enhancer) and the liver-specific promoter alpha 1-antitrypsin promoter, preferably the human alpha 1-antitrypsin promoter (paragraph 0058). It is stated that the skilled person will also appreciate that, as long as the length of the viral genome does not exceed the packing size limit of the viral capsid, the viral genome of the AAV vector may comprise part or all of the genomic sequence, in which case, the coding region will be interrupted by intronic regions (paragraph 0067). It is taught that the promoter and the nucleotide sequence encoding the protein can be separated by an intron (paragraph 0062). The expression cassette contains the liver-specific enhancer HCR, the liver-specific promoter hAAT, an intron and the nucleic acid (paragraph 0195). In BMP4 high fat-fed mice, there was a dramatic increase in the brown adipose marker UCP1 (paragraph 02221). The AAV vector can be administered to the subject by conventional methods which require the formulation of said vectors in a pharmaceutical composition (paragraph 0100) which include a pharmaceutically acceptable carrier and excipients (paragraph 0107). The AAV vector may be formulated for parenteral administration (paragraph 0109). The AAV vector can be packaged into infectious viral particles when present in a host cell that has been transfected with a vector (paragraph 0040; 0151).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ishigaki et al., Zadeh et al. and Smith et al. and administer a vector comprising UCP1 to a subject with lipodystrophy. One skilled in the art would have been motivated to administer the vector to this patient population as Ishigaki et al. teaches the vector potential therapy for the metabolic syndrome in obese and diabetic individuals, Smith et al. teaches administration of vectors which result in increased UCP1 in patients with obesity, insulin resistance, type 2 diabetes, liver cirrhosis and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) and Zadeh et al. teaches that patients with lipodystrophy group are characterized by severe insulin resistance, severe hypertriglyceridemia, low HDL cholesterol, low leptin and diponectin, ectopic fat accumulation, non-alcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Therefore, one skilled in the art would have been motivated to administer the vector to treat one of the symptoms characterized in lipodystrophy as suggested by the prior art. Since all of Ishigaki et al., Zadeh et al. and Smith et al. suggest non-alcohol fatty liver disease and NASH can be treated, one would expect that at a minimum these symptoms could be inhibited.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ishigaki et al., Zadeh et al. and Smith et al. and utilize the vector of Smith et al. to deliver a nucleic acid encoding UCP1. One skilled in the art would have been motivated to utilize this vector as Ishigaki et al. focuses on hepatic UCP1 expression and Smith et al. utilizes an AAV vector in which the polynucleotide is under the control of a liver-specific promoter which allow for expression of the nucleic acid sequence in specific tissues such as hepatocytes. Therefore, since Ishigaki et al. specially desires hepatic UCP1 expression one skilled in the art would have been motivated to utilize an AAV vector which would allow for expression in the liver.
Regarding the claimed vector, the promoter is a liver specific promoter. Regarding SEQ ID NO. 2, Ishigaki et al. teaches UCP1. GenBank teaches the sequence of human UCP which has 100% identity to instantly claimed SEQ ID No. 2. Smith et al. teaches the inclusion of an intron which reads on the intron of claim 1. Smith et al. teaches that inclusion of the genomic sequence the coding region would be interrupted by intronic regions. Therefore, inclusion of all of the genomic sequence would possess the intron in the same position as recited in claims 54-55. See alignment below where Qy is instant SEQ ID NO: 2 and Db is the sequence from GenBank:
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Regarding claims 48-49, Smith teaches both AAV8 or AAV3 vector can be used. It would have been obvious to one of ordinary skill in the art to try any of the specifically taught AAV vectors as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Regarding claim 50, Smith et al. teaches the same promoters.
Regarding claim 51-52, Smith et al. teaches an HCR enhancer.
Regarding claim 57, Zadeh et al. teaches patients with lipodystrophy include those with a partial lipodystrophy.
Regarding claim 58-59, Ishigaki et al. teaches administration of the vector. Smith et al. teaches the AAV vector can be incorporated into a pharmaceutical composition with conventional components like a carrier or excipients and that the vector can be administered parenterally. All of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007).
Regarding claim 60, Smith et al. teaches the vector is present in the host cell.
Claims 1, 48-54 and 56-60 are rejected under 35 U.S.C. 103 as being unpatentable over Ishigaki et al. in view of GenBank, Zadeh et al. and Smith et al. as applied to claims 1, 48-52, 54 and 56-60 above and in further view of Gray (WO2019153009)
Applicant Claims
The instant application claims the enhancer has the sequence of SEQ ID No: 7 or SEQ ID NO: 8.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Ishigaki et al., GenBank, Zadeh et al. and Smith et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While a liver specific enhancer including an HCR enhancer is taught, an enhancer of SEQ ID NO: 8 is not expressly taught. However, this deficiency is cured by Gray.
Gray is directed to transcription regulatory elements and uses thereof. Claimed is a ApoE-HCR enhancer or a functional portion thereof. The functional portion has a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO:2 (claims 12-15).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ishigaki et al., Zadeh et al., Smith et al. and Gray and utilize a functional fragment of an ApoE hepatic control region enhancer. Since the functional fragment still possess the function of the HCR enhancer, there is a reasonable expectation of success.
The ApoE-HCR enhancer of SEQ ID NO: 2 has 100% similarity to instantly claimed SEQ ID NO: 8 as shown in the alignment below:
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Claims 1, 48-52 and 54-60 are rejected under 35 U.S.C. 103 as being unpatentable Ishigaki et al. in view of GenBank, Zadeh et al. and Smith et al. as applied to claims 1, 48-52, 54 and 56-60 above and in further view of Ronzitti et al. (WO2020208032).
Applicant Claims
The instant application claims the vector is an AAV8 vector comprising a TBG or a TTR promoter operably linked to the nucleic acid encoding UCP1, wherein the vector further comprises a CRM8 enhancer, and wherein an intron is located between exons 1 and 2 of the nucleic acid encoding UCP 1.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Ishigaki et al., GenBank, Zadeh et al. and Smith et al. are set forth above. Ishigaki et al. and GenBank suggest the nucleic acid which fully encodes UCP1 which would include the intron located between exons 1 and 2. Smith et al. teaches an AAV vector which can be an AAV8 vector and can comprise a TBG or TTR promoter.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While an liver-specific enhancers are suggested, a CRM8 enhancer is not expressly taught. However, this deficiency is cured by Ronzitti et al.
Ronzitti et al. is directed to hybrid promoters for muscle expression. Liver selective enhancers include an HS-CRM8 enhancer (page 2). Use of AAV8 vectors are taught (page 4).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ishigaki et al., Zadeh et al., Smith et al. and Ronzitti et al. and utilize a CRM8 enhancer. One skilled in the art would have been motivated to utilize a CRM8 enhancer as it is a known liver-selective enhancer as taught by Ronzitti et al. Since Ishigaki et al. teach expression in the liver and Smith et al. suggests the use of liver-specific/selective enhancers, there is a reasonable expectation of success. Since Ronzitti et al. teaches the use with an AAV8 vector there is a reasonable expectation of success.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636