DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 23-26 are pending.
Preliminary Amendments
Applicant’s preliminary amendment filed on 03/05/2026 is acknowledged. The claims were amended to remove the non-elected species. The title was amended to remove the non-elected species.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 for application RU2018147082, filed 12/27/2018. This is a 371 of PCT/RU2019/000991, filed 12/20/2019.
Election/Restrictions
Applicant’s election without traverse of SEQ ID NO: 1 in the reply filed on 03/05/2026 is acknowledged.
Claim(s) 23-26 are under consideration.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency #1 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
See Pages 12, 13, 14, 38, 40, 41, 42, 43, 45, 46, 48, 49, 50, 52, 53, 54, 89, 90, 91 of the substitute specification filed 02/05/2024.
Specific deficiency #2 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Specific deficiency #3 – Nucleotide sequences appearing in claim 25 are not identified by sequence identifiers.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
A statement of Incorporation by Reference paragraph.
An amendment to the claims in compliance with 37 CFR 1.121 to add the related SEQ ID NOs: for the sequences in claim 25.
Specification
Minor informalities
The disclosure is objected to because of the following informalities:
There is a word, composed of letters from the Russian alphabet, not translated, in line 2 of page 16 between “therapy DNA vector…” and “VTvaf17-P4HA2”.
Appropriate correction is required.
Embedded Hyperlinks
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See pages 8, 56, 57, 58, 59, 61, 62, 63, 64, 66, 67, 70, and 82 of the substitute specification filed on 02/05/2024.
Trade Names, Trademarks, and other Marks used in commerce
The use of the term(s):
Genbank (on pages 19, 20, 21, 22, 23, 30, 45, 46, 47, 49, 50, 51, 53, 54, and 74);
Lipofectamine 3000 (on pages 44, 46, 47, 49, 50, 51, 53, and 54);
Opti-MEM (on page 44);
Trizol (on page 44);
SYBR GreenQuantitect (on page 45);
ChemWell (on pages 56, 57, 58, 59, 60, 61, 63, 64, 65, and 67);
Sepharose (on page 78);
Superdex 200 (on page 79); and
SuperFect (on pages 55, 57, 58, 59, 60, 61, 62, and 63).
which is/are a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim(s) 23-26 are objected to because of the following informalities:
Regarding claim 23:
“VTvafl 7” in line 2 and 10 should recite “VTvaf17”; and
“COLIAI” in line 8 and 10 should recite “COL1A1”.
Regarding claim 24:
“COL1AI” in line 4 should recite “COL1A1”.
Regarding claim 25:
“COL1AI” in line 4, 8 and 22 should recite “COL1A1”; and
“… as per claim 23 is cloned to the gene therapy…” in line 7 should recite “…as per claim 23 is cloned into the gene therapy…”.
Regarding claim 26:
“VTvafI7” in line 2, 11, and 16 should recite “VTvaf17”; and
Regarding claim(s) 25 and 26:
MPEP 608.01(m) recites, “where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).”
Both claims contain steps that are not separated by indentation thus making it difficult to understand the process of production and use, claim 25 and 26 respectively.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Improper Dependent
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 24 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 24, claim 23 recites a gene therapy DNA vector of SEQ ID No. 1. Claim 24 recites “… the gene therapy DNA vector being unique due to a fact that VTvaf17-COL1AI per claim 23 uses the nucleotide sequences that are not antibiotic resistance genes, viral genes, or regulatory elements of viral genomes as structure elements, which ensures a safe use for the gene therapy in humans and animals.” This is inherent to claim 23 and does not further limit the scope of claim 23 because the instant specification describes the vector of SEQ ID No. 1 as not having antibiotic resistance genes, virus genes, or regulatory elements of viral genomes as structural elements (see page 10 section III), and page 31, paragraph 1).
Therefore, claim 24 is rejected for failing to further limit the subject matter of claim 23.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a) – Scope of enablement
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.
Claim(s) 23-26 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
a DNA vector VTvaf17-COL1A1 that has the nucleotide sequence of SEQ ID NO: 1; and
a method of producing a DNA vector, comprising cloning a coding region of COL1A1 into gene therapy DNA vector VTvaf17 to produce DNA vector VTvaf17-COL1A1 that has the nucleotide sequence of SEQ ID NO: 1;
does not reasonably provide enablement for a gene therapy DNA vector from DNA vector VTvaf17-COL1A1 that has the nucleotide sequence of SEQ ID NO: 1; isolating total RNA from a human biological tissue sample, followed by a reverse transcription reaction and a PCR amplification using the obtained oligonucleotides and cleaving an amplification product by corresponding restriction endonucleases, and cloning to the gene therapy DNA vector VTvaf17 is carried out at NheI and HindIII restriction sites to result in the production of DNA vector VTvaf17-COL1A1 that has the nucleotide sequence of SEQ ID NO: 1; using a VTvaf17 gene therapy vector carrying a therapeutic gene of COL1A1 to treat diseases associated with disorders of formation of the extracellular matrix of the skin and other organs, the skin structure, the wound healing disorders; using a VTvaf17 gene therapy vector carrying a therapeutic gene of COL1A1 to prevent skin ageing caused by internal and external factors; or using a VTvaf17 gene therapy vector carrying a therapeutic gene of COL1A1 to treat hereditary and acquired connective tissue diseases, including Ehlers-Danlos syndrome, epidermolysis bullosa, Caffey disease, osteogenesis imperfecta, pathological scarring, formation of scars, superficial epidermal cysts, and hyperpigmentation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention
Claim 23 is interpreted as being drawn to DNA vector VTvaf17-COL1A1 that has the nucleotide sequence of SEQ ID NO: 1. The nature of the invention is complex in that the claim requires the enabled use of the DNA vector as a gene therapy DNA vector for “treatment of diseases associated with disorders of formation of an extracellular matrix of a skin and other organs, a skin structure, wound healing disorders, for prevention of a skin ageing caused by internal and external factors, for treatment of hereditary and acquired connective tissue diseases, including Ehlers-Danlos syndrome, epidermolysis bullosa, Caffey disease, osteogenesis imperfecta, pathological scarring, a formation of scars, superficial epidermal cysts, and a hyperpigmentation alopecia. Thus, the DNA vector, VTvaf17-COL1A1 must be capable of treating and preventing the recited disorders.
Claim 25 is interpreted as a method of producing a gene therapy DNA vector to obtain DNA vector VTvaf17-COL1A1 that has the nucleotide sequence of SEQ ID NO: 1. The nature of the invention is complex in that the specific sequence must be obtained by the production method, yet the steps of the method are the following: “isolating total RNA from a human biological tissue sample, followed by a reverse transcription reaction and a PCR amplification using the obtained oligonucleotides and cleaving an amplification product by corresponding restriction endonucleases, and cloning to the gene therapy DNA vector VTvaf17 is carried out at NheI and HindIII restriction sites.” Thus, RNA from any human biological sample must provide the claimed sequence of COL1A1. Furthermore, one must be able to use any “corresponding restriction endonucleases” in the method. Moreover, the nature of the invention is complex in that the DNA vector must be capable of being used as a gene therapy DNA vector.
Claim 26 is interpreted as being drawn to a method of using DNA vector VTvaf17-COL1A1 that has the nucleotide sequence of SEQ ID NO: 1 to treat or prevent a disease associated disorder. The claim is interpreted as being drawn to the step of (i) transfecting cells of human or animal organs and tissues with the DNA vector; (ii) injecting human or animal autologous cells of a patient or animal transfected with the DNA vector into human or animal organs and tissues; (iii) injecting organs and tissues of a human or animal with the DNA vector; or (iv) a combination thereof. The nature of the invention is complex in that the DNA vector must be capable of treating “diseases associated with disorders of formation of the extracellular matrix of the skin and other organs, the skin structure, the wound healing disorders,” must be capable of preventing “skin ageing caused by internal and external factors”, and must be capable of treating “hereditary and acquired connective tissue diseases, including Ehlers-Danlos syndrome, epidermolysis bullosa, Caffey disease, osteogenesis imperfecta, pathological scarring, formation of scars, superficial epidermal cysts, and hyperpigmentation”.
Breadth of the claims
Claim 23 is broad in that the DNA vector, VTvaf17-COL1A1 must be capable of treating and preventing any disease associated disorder recited in those claims.
Claim 25 is broad in that it encompasses the use of any human biological tissue sample, and any corresponding restriction endonucleases to provide the claimed sequences, which must be capable of being used to treat or prevent any disease associated disorder recited in claim 23.
Claim 26 is broad in that it encompasses the treatment or prevention of any disease associated disorder of those recited in the claim, in any human or animal by transfecting or injecting any organ or tissue with the VTvaf17-COL1A1 DNA vector.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples:
The specification discloses purposes:
“The purpose of the invention also includes the construction of strains carrying these gene therapy DNA vectors for the development and production of these gene therapy DNA vectors on an industrial scale. The specified purpose is achieved by using the produced gene therapy DNA vector based on the gene therapy DNA vector VTvaf17 for treatment of diseases associated with disorders of formation of the extracellular matrix of the skin and other organs, skin structure, wound healing disorders, for prevention of skin ageing caused by internal and external factors, for treatment of hereditary and acquired connective tissue diseases, including Ehlers-Danlos syndrome, epidermolysis bullosa, Caffey disease, osteogenesis imperfecta, pathological scarring, formation of scars, superficial epidermal cysts, and hyperpigmentation while the gene therapy DNA vector VTvaf17-COL1A1 contains the coding region ofCOL1A1 therapeutic gene cloned to gene therapy DNA vectorVTvaf17 with the nucleotide sequence SEQ ID No. 1…”, (see page 10, paragraph 8 to page 11, paragraph 1).
“Moreover, these data suggest that insufficient expression of proteins encoded by COL1A1… genes included in the group of genes is associated not only with pathological conditions, but also with a predisposition to their development. Also, these data indicate that insufficient expression of these proteins may not appear explicitly in the form of a pathology that can be unambiguously described within the framework of existing clinical practice standards (for example, using the ICD code), butat the same time cause conditions that are unfavourable for humans and animals and associated with deterioration in the quality of life. Analysis of approaches to increase the expression of therapeutic genes implies the practicability of use of different gene therapy vectors.”, (page 6, paragraphs 3-4).
The specification discloses that mutations in COL1A1 gene:
“It was found that individual mutations in genes encoding collagens (for example, type I, III, or V) or collagen modifying enzymes (for example, lysyl hydroxylase, collagenase) cause different forms of Ehlers-Danlos syndrome that affect connective tissues (systemic dysplasia of the connective tissue) supporting the skin, bones, blood vessels, and other organs.” (page 3, paragraph 1).
“A mutation in the COL1A1 gene that causes infantile cortical hyperostosis or Caffey disease is described. This condition features soft tissues oedema (for example, muscles), pain, and excessive formation of new bone tissue (hyperostosis). Bone abnormalities mainly affect the jawbone, clavicles, (collarbones) and diaphysis of long limb bones.”, (page 3, paragraph 3).
“Another hereditary disease due to mutations in the collagen genes and causing diffuse abnormal brittleness of bones, sometimes accompanied by sensorineural hearing loss, blue scleros, imperfect dentinogenesis, and hypermobility of joints is a brittle bone disease. 90% of people with one of the main types of disease have mutations in COL1A1 or COL1A2 genes.”, (page 3, paragraph 4).
“The presence of COL1A1… protein confirms the efficiency of expression of therapeutic genes in eukaryotic cells and the possibility of increasing the protein concentration using the gene therapy DNA vector based on gene therapy DNA vector VTvaf17 carrying the therapeutic gene selected from the group of COL1A1… genes.”, (page 33, paragraph 2).
Thus, the specification envisions increasing expression of COL1A1 by gene therapy to treat any defect in the gene (title, abstract, and page 6 paragraphs 3-4). The specification envisions transfecting cells with the VTvaf17-COL1A1 vector of SEQ ID NO: 1, or injecting cells that have been transfected (page 33, paragraph 2).
The specification discloses that amplification products of COL1A1 were cleaved with restriction endonucleases NheI and HindIII for cloning into VTvaf17, which was also cleaved with NheI and HindIII restriction endonucleases (page 32, paragraph 1). No corresponding restriction endonucleases are taught, other than the direct correspondence of NheI to NheI, and HindIII to HindIII.
Example 1 is directed to the production of VTvaf17-COL1A1 by RT-PCR and restriction digest to clone the COL1A1 sequence into VTvaf17. See Fig. 1A.
Example 9 and Example 17 are directed to demonstrate RNA and Protein can be expressed from VTvaf17-COL1A1, which has been transfected into HDFa human primary dermal fibroblast cells. See Figs. 2 and 10.
Example 29 demonstrates combined use of DNA vector VTvaf17-COL1A1 carrying the COL1A1 gene, gene therapy DNA vector VTvaf17-COL1A2 carrying the COL1A2 gene, gene therapy DNA vector VTvaf17 P4HA1 carrying the P4HA1 gene, gene therapy DNA vector VTvaf17-P4HA2 carrying the P4HA2 gene in order to increase the expression level of the COL1A1, COL1A2, P4HA1, and P4HA2 proteins in mammalian tissues, more specifically, rat skin of three rats. Protein levels were assayed as previously mentioned in Example 17, and results showed the efficiency of combined use of gene therapy DNA vector VTvaf17-COL1A1, gene therapy DNA vector VTvaf17-COL1A2, gene therapy DNA vector VTvaf17 P4HA1, and gene therapy DNA vector VTvaf17-P4HA2 and practicability of their use for the increase of the expression level of therapeutic proteins in mammalian tissues. See Fig. 22.
No working examples are directed to the measurement of therapeutic or preventive outcomes with VTvaf17-COL1A1. The asserted therapeutic efficacy relies solely upon the expression of mRNA and protein, as well as the protein level of COL1A1 when in combination with other DNA vectors, and not alone, when biopsies were taken from rats. No therapeutic outcome is provided for diseases associated with disorders of formation of the extracellular matrix of the skin and other organs, the skin structure, the wound healing disorders; no preventative outcome is provided for skin ageing caused by internal and external factors; and no therapeutic outcome is provided for hereditary and acquired connective tissue diseases, including Ehlers-Danlos syndrome, epidermolysis bullosa, Caffey disease, osteogenesis imperfecta, pathological scarring, formation of scars, superficial epidermal cysts, and hyperpigmentation.
Predictability and state of the art
Looking to the art on gene therapy with COL1A1, Niyibizi et al (Gene therapy approaches for osteogenesis imperfecta, Gene Therapy, Vol. 11, Pages 408-416, published January 15th, 2004) teach that osteogenesis imperfecta results from over 100 different mutations that have been identified in the COL1A1 and Col1A2 genes where the majority of the mutations are dominant negative (e.g., page 408, paragraph bridging columns). Thus, expression of the mutant form of the encoded proα1(I) or proα2(I) proteins interferes with the formation of normal collagen, resulting in the osteogenesis imperfecta phenotype (e.g., Niyibizi et al. page 408, paragraph bridging columns; paragraph bridging pages 412-413; page 415, left column, 1st full paragraph). Niyibizi et al teach that gene therapy approaches for osteogenesis imperfecta will require silencing of the expression of the genes that encode abnormal collagen alleles before replacement of the mutated gene; however, there are difficulties in the design of antisense gene therapy to target only the expression of the abnormal alleles (i.e., dominant negative mutant versions) (e.g., page 408, paragraph bridging columns; paragraph bridging pages 412-413; page 415, left column, 1st full paragraph).
Looking to the art on strategies for therapies involving osteogenesis imperfecta, Marom et al (Pharmacological and biological therapeutic strategies for osteogenesis imperfecta, American Journal of Medical Genetics Part C (Seminars in Medical Genetics), Vol. 172C, pages 367-383, published December 12th, 2016) teach that some success with gene therapy to express COL1A1 in patient-derived marrow stromal cells has only been successful with an AAV vector designed to disrupt the endogenous COL1A1 gene is used (e.g., page 377, Gene Therapy). Further, Marom et al teach that cell-therapy to increase type I collagen is considered experimental and controversial with respect to the risks and benefits in patients with OI, and its clinical use is limited by the toxicity associated with bone marrow transplantation and lack of suitable donors (e.g., page 377, Cell Therapy).
The use of cell or gene therapy to treat diseases, such as osteogenesis imperfecta, by expressing COL1A1 gene is underdeveloped and unpredictable. Accordingly, one would have recognized that it would have been unpredictable to treat or prevent any disease associated disorder, including osteogenesis imperfecta, by delivering a plasmid vector encoding COL1A1.
It would have been unpredictable to use any human biological tissue sample to obtain RNA for RT-PCR to arrive at the coding sequences present in SEQ ID NO: 1. The COL1A1 coding sequence contains polymorphic positions in the human population (see page 33, paragraph 1).
Amount of experimentation necessary:
A large quantity of experimentation would be required to use the claimed vector to treat or prevent all recited and encompassed disease associated disorders. One must test the vector in an appropriate model system with an appropriate outcome measure that is specifically directed to therapeutic efficacy, rather than merely reporting on the presence of protein or mRNA expression. Treatment of “diseases associated with disorders of formation of the extracellular matrix of the skin and other organs, the skin structure, the wound healing disorders,”; Prevention of “skin ageing caused by internal and external factors”; treatment of “hereditary and acquired connective tissue diseases, including Ehlers-Danlos syndrome, epidermolysis bullosa, Caffey disease, osteogenesis imperfecta, pathological scarring, formation of scars, superficial epidermal cysts, and hyperpigmentation” will require different outcomes to be measured. This type of experimentation would require a large amount of inventive effort and is not routine in the art.
Further experimentation would be required to identify appropriate human tissue samples from subject that have coding sequence identical to that contained in instant SEQ ID NO: 1, and identify corresponding restriction endonucleases for use in the claimed method.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 23-26 are not considered to be fully enabled by the instant specification.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 23-26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Savelieva et al (RU 2707537 C1, Published November 27th, 2019; machine translation of the specification included as an NPL).
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Regarding claim 23, Savelieva et al discloses in FIG. 1A (page 55 of FOR document) a gene therapy DNA vector, VTvaf17-COL1A1, as well as SEQ ID NO:3 is 100% identical to instant SEQ ID NO: 1 (page 49 of FOR document).
Regarding claim 24, Savelieva et al discloses, “Each of the created gene therapeutic DNA vectors: VTvaf17-COL1A1, or VTvaf17-COL1A2, or VTvaf17-BMP2, or VTvaf17-BMP7 due to the limited size of the vector part of VTvaf17, not exceeding 3200 bp, has the ability to efficiently penetrate cells and express the cloned it contains a target gene selected from the group of genes COL1A1, COL1A2, BMP2, BMP7. The gene therapy DNA vector lacks nucleotide sequences of viral origin and lacks antibiotic resistance genes, making it safe to use for genetic therapy in humans and animals.”, (see page 4, paragraph 1).
Regarding claim 25, Savelieva et al discloses in Example 1 a method of producing the DNA vector, VTvaf17-COL1A1, carrying the target gene COL1A1. More specifically, “The gene therapy VTvaf17-COL1A1 DNA vector was constructed by cloning the coding portion of the COL1A1 gene into VTvaf17 DNA vector at restriction sites NheI and HindII. The coding part of the COL1A1 gene is 4422 bp in size. obtained by isolating total RNA from a biological sample of human tissue, followed by a reverse transcription reaction using a commercial Mint-2 kit (Eurogen, Russia) and created oligonucleotides
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… As a result, the DNA vector VTvaf17-COL1A1 with the nucleotide sequence of SEQ ID No. 1 was obtained, carrying the target gene, namely, the COL1A1 gene, 4422 bp in size. with the possibility of selection without antibiotics with the structure depicted in FIG. 1.A.”. (See page 19 of the FOR document to see image inserts of the restriction sites and oligonucleotides, which is missing from pages 13 and 14 of the translated document due to machine translation of images being removed).
Regarding claim 26, Savelieva et al discloses in Example 15, the transfection of VTvaf17-COL1A1 into autologous fibroblasts isolated from patient skin, and injection back into the patient. More specifically, “The patient was introduced with a patient’s culture of autologous fibroblasts of this patient transfected with VTvaf17-COL1A1 gene therapy vector DNA and a placebo representing a culture of patient’s autologous fibroblasts transfected with VTvaf17 gene therapy DNA vector was carried out by the tunnel method into the forearm with a 30G needle with a length of 13 mm to a depth of about 3 mm . The concentration of modified autologous fibroblasts in the injected suspension was approximately 5 million cells per 1 ml of suspension, the number of introduced cells did not exceed 15 million. The foci of the introduction of autogenic fibroblast culture were located at a distance of 8-10 cm from each other.”, (see page 26, Example 15, paragraph 5).
Therefore, claim(s) 23-26 are anticipated by Savelieva et al.
Claim(s) 23-26 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Savelieva et al (US 11352639 B2, Foreign Priority Date of September 4th, 2018).
The applied reference has a common inventor (Natalia Savelieva) and applicant(s) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Of note: Savelieva et al has two additional inventors, Vasily Nikolaevich Lazarev and Galina Vasilievna Shmarina; and an additional applicant, OBSCHESTVO S OGRANICHENNOI OTVETSTVENNOSTJU “ALLEL TSENTR INNOVATSIONNYKH BIOTEKHNOLOGY”.
Regarding claim 23, Savelieva et al discloses, “This gene therapy DNA vector that has the coding region of COL1A1 therapeutic gene cloned to gene therapy DNA vector VTvaf17 resulting in gene therapy DNA vector VTvaf17-COL1A1”. (see column 5, lines 4-7).
More specifically, SEQ ID NO: 3 of Savelieva et al is 100% identical to the instantly claimed SEQ ID NO: 1.
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Regarding claim 24, Savelieva et al discloses, “Each of the constructed gene therapy DNA vectors based on gene therapy DNA vector VTvaf17 carrying the COL1A1, COL1A2, BMP2, or BMP7 therapeutic gene namely gene therapy DNA vectors VTvaf17-COL1A1, or VTvaf17-COL1A2, or VTvaf17-BMP2, or VTvaf17-BMP7 due to the limited size of VTvaf17 vector part not exceeding 3200 bp has the ability to efficiently penetrate into human and animal cells and express the therapeutic gene selected from the group of COL1A1, COL1A2, BMP2, or BMP7 genes. At the same time, nucleotide sequences that are not antibiotic resistance genes, virus genes, or regulatory elements of viral genomes are used as structure elements, which ensures its safe use for gene therapy in humans and animals.”, (see column 5, lines 20-33).
Regarding claim 25, Savelieva et al discloses, “ The method of production of gene therapy DNA vector based on gene therapy DNA vector VTvaf17 carrying the therapeutic gene selected from the group of COL1A1, COL1A2, BMP2, and BMP7 is performed as follows: 1. the coding region of COL1A1 gene (4422 bp), or COL1A2 gene (4128 bp), or BMP2 gene (1219 bp), or BMP7 gene (1322 bp) is obtained by isolating total RNA from a biological sample of normal tissue, followed by a reverse transcription reaction and PCR amplification using the oligonucleotides obtained by the chemical synthesis method for this purpose, followed by the cleavage of amplification product by restriction endonucleases NheI and HindiIII…The obtained gene therapy DNA vector VTvaf17 carrying the therapeutic gene selected from the group of COL1A1, COL1A2, BMP2, and BMP7 genes was transformed by electroporation of Escherichia coli strain SCS110-AF, with antibiotic-free selection of the obtained clones.”, (see column 11, lines 53-65 and column 12, lines 5-10).
Regarding claim 26, Savelieva et al discloses, “In order to confirm the practicability of use of the constructed gene therapy DNA vector VTvaf17-COL1A1, … , the following was performed: a. transfection of different human cell lines with gene therapy DNA vectors, b. injection of gene therapy DNA vectors into different human and animal tissues, c. injection of a mixture of gene therapy DNA vectors into animal tissues, d. injection of autologous cells transfected with gene therapy DNA vectors into human tissues.”, (column 12, lines 34-46).
Therefore, claim(s) 23-26 are anticipated by Savelieva et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 23 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11352639 B2 (hereinafter ‘639). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claim(s) 23 and 24, which recite:
23. A gene therapy DNA vector based on a gene therapy DNA vector VTvafl 7 for treatment of diseases associated with disorders of formation of an extracellular matrix of a skin and other organs, a skin structure, wound healing disorders, for prevention of a skin ageing caused by internal and external factors, for treatment of hereditary and acquired connective tissue diseases, including Ehlers-Danlos syndrome, epidermolysis bullosa, Caffey disease, osteogenesis imperfecta, pathological scarring, a formation of scars, superficial epidermal cysts, and a hyperpigmentation alopecia, wherein the gene therapy DNA vector has a coding region of a therapeutic gene COLIAI cloned to the gene therapy DNA vector VTvafi7 resulting in a gene therapy DNA vector VTvafl 7-COLIAI that has a nucleotide sequence SEQ ID No. 1.
24. The gene therapy DNA vector based on the gene therapy DNA vector VTvaf17 carrying COL1A1 therapeutic gene as per claim 23, the gene therapy DNA vector being unique due to a fact that VTvaf17-COL1AI as per claim 23 uses the nucleotide sequences that are not antibiotic resistance genes, virus genes, or regulatory elements of viral genomes as structure elements, which ensures a safe use for the gene therapy in humans and animals.
Claim 1 of ‘639, which recites:
1. A DNA vector selected from the group consisting of (i) DNA vector VTvaf17-COL1A1 that has the nucleotide sequence of SEQ ID NO: 1; (ii) DNA vector VTvaf17-COL1A2 that has the nucleotide sequence of SEQ ID NO: 2; (iii) DNA vector VTvaf17-BMP2 that has the nucleotide sequence of SEQ ID NO: 3; and (iv) DNA vector VTvaf17-BMP7 that has the nucleotide sequence of SEQ ID NO: 4.
Claim 1 of ‘639 recites a DNA vector that has the nucleotide sequence of SEQ ID NO:3, which is identical to instant SEQ ID NO: 1, the claimed vector of instant claim 23. Claim 1 of ‘639 includes a nucleotide sequence which does not contain antibiotic resistant genes, virus genes, or regulatory elements of viral genomes as structures, thus instant claim 24 is anticipated by SEQ ID NO: 3 of the ‘639 claim 1. (see alignment below).
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Thus, claims 23 and 24 are anticipated by claim 1 of the ‘639 patent.
Conclusion
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637