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 .
Detailed Action
Claims 1-20 are currently pending as per claims filed on June 30, 2023. Claims 1, 12 and 20 are independent claims.
Therefore, claims 1-20 are currently under examination to which the following grounds of rejection are applicable.
Priority
Applicant’s claim for the benefit of a prior-filed parent provisional application 63/357,275 filed on 06/30/2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/14/2023 and 11/01/2023 was filed after the mailing date of the non-final office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification Objection
The disclosure is objected to because of the following informalities: inclusion of an "appendix" (e.g. Appendix A) which contains a copy of non-patent literature is inappropriate (pg 41-52). Please remove it from the Specification. Appropriate correction is required.
Claim Objections
Claim 7 and 17 objected to because of the following informalities: TMPRRS2 is recited. However, it appears the applicant’s intent was to recite TMPRSS2. Appropriate correction is required.
Claim Rejections - 35 USC § 112
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 1-19 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.
M.P.E.P. § 2163 recites, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A), above), reduction to drawings (see i)(B), above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.” Further, the written description inquiry is limited to that which is contained within the four corners of the specification, not the extent to which the skilled artisan, given his or her knowledge of the art, would have considered it to expand with only routine experimentation. See Ariad Pharms. Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc); see also id. at 1352 (“[I]t is the specification itself that must demonstrate possession. a description that merely renders the invention obvious does not satisfy the requirement.").
Claim 1 is drawn to a genetically modified transgenic swine comprising at least one modified Transmembrane protease, serine (TMPRSS) gene as compared to a non-genetically modified swine with wild-type TMPRSS gene, wherein expression of functional gene products of the at least one modified TMPRSS gene in the genetically modified transgenic swine is decreased as compared to the non-genetically modified swine. The claims are broadly directed to a vast genus of genetically modified transgenic swine comprising a genus of modifications of the TMPRSS that result in decreased expression of the TMPRSS gene product as compared to the non-genetically modified swine. The claims broadly encompass any genetic modification (genetic modifications by culture, UV light, selective cross breeding, CRISPR and others) wherein the modification may be in somatic cells and not necessarily within the genome of the swine, and wherein the genus of genetic modifications may involve a single base pair, deleting an exon, adding a new region of DNA, deleting an intron or deleting the full TMPRSS gene such that the genetically modified transgenic swine exhibits a phenotype characterized by decreased expression of the TMPRSS gene product relative to the non-genetically modified swine.
There is not structure/function correlation for the claimed genus of genetic modifications (somatic or genomic genetic modifications by culture, UV light, selective cross breeding, CRISPR and others), the claimed genus of at least one modified TMPRSS gene (point mutations, deletions, additions and others) resulting in decreased expression of functional gene products of the at least one modified TMPRSS compared to the non-genetically modified swine, other than for knocking out (KO) the TMPRSS2 gene in the genome swine via a CRISPR/Cas system.
The Specification teaches a genetically modified swine wherein exon 2 of the swine TMPRSS2 gene is modified to result in a knockout of the TMPRSS2 gene causing lack of expression of the gene product (para 0021-0024; FIG 6A-D). Moreover, data suggests the knockout swine exhibits a phenotype of resistance to influenza virus as evidenced by decreased viral load in influenza-challenged challenged KO swine compared to wildtype swine (FIGs 9A-B, 10A-B, 11A-B). The specification teaches the location of guide RNAs which flank exon 2 of the TMPRSS2 gene and the mixtures of specific guide RNAs would result in the removal of exon 2 and the start codon when co-injected (FIG 6A-B). The specification shows the use of injection for inserting CRISPR/Cas9 RNA into a zygote and the resulting TMPRSS2-KO swine (FIG 6C-D).
However, the specification does not disclose a reduction to practice of a genetically modified swine comprising a genus of modified TMPRSS gene with decreased gene product other than a knock out TMPRSS2 gene at exon 2 that would exhibit the phenotype of less susceptibility and shedding significantly less influenza virus compared to non-genetically modified swine. The specification contemplates the generation of a genetically modified swine (para 0071-0079) and the assortment of TMPRSS genes and corresponding exons that may be targeted to generate KO swine (para 0081-0092). Moreover, the specification describes that the genetically modified swine may have a resulting phenotype of increased resistance to influenza, as demonstrated by assessment via various experimental assays (para 0091-0097), however the Specification does not exemplify that genetic modification of other TMPRSS genes would result in the desired phenotype. Outside of this scope of enablement, there is no minimal or maximal physiological or phenotypic result which would necessarily tell a skilled artisan the genetically modified swine has developed resistance to influenza.
With regards to the modifications to TMPRSS genes, the specification mentions many other TMPRSS genes and their corresponding exons that may be targeted, however the specification fails to demonstrate if other TMPRSS genes and exons, besides TMPRSS2 with modification at exon 2, would result in the swine with less susceptible to an influenza virus and sheds significantly less influenza virus TMPRSS2.
Applicant were referred to the guidelines for Written Description Requirement published January 5, 2001 in the Federal Register, Vol.66, No.4, pp.1099-1110 (see http://www.uspto.gov). 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 possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics (as it relates to the claimed invention as a whole) such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. See, e.g., Pfaff v. WellsElectronics, Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharmaceutical, 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
The “written description” requirement may be satisfied by using such descriptive means as words, structures, figures, diagrams, formulas, etc., that fully set forth the claimed invention. See Noelle v. Lederman, 355 F.3d 1343, 1349, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) and Lockwood v. American Airlines, Inc., 107 F.3d at 1572, 41 U.S.P.Q.2d at 1966. A definition by function alone “does not suffice” to sufficiently describe a coding sequence “because it is only an indication of what the gene does, rather than what it is.” Regents of the University of California v. Eli Lilly & Co., 119 F.3 at 1568, 43 USPQ2d at 1406 (Fed. Cir. 1997) (discussing Amgen Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 U.S.P.Q.2d 1016 (Fed. Cir. 1991)). In Fiers v. Ravel, 984 F.2d at 1169-71, 25 U.S.P.Q.2d at 1605-06 (1993), the CAFC found that “a mere wish or plan for obtaining the claimed chemical invention” is not sufficient to describe a chemical invention (discussed in Eli Lilly at 1404).
In the instant application, only one TMPRSS gene modification and one exon is disclosed. Therefore, the limited disclosure in the specification is not deemed sufficient to reasonably convey to one skilled in the art that the applicants were in possessions of the huge genera recited in the claims at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genera.
.
Scope of Enablement
Claim 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the the specification, while being enabling for
A genetically modified transgenic swine whose genome comprises a knocked out transmembrane protease, serine 2 (TMPRSS2) gene, wherein expression of functional gene products is decreased as compared to the non-genetically modified swine,
does not reasonably provide enablement for (1) a genus of genetic modifications (somatic or genomic genetic modifications by culture, UV light, selective cross breeding, CRISPR and others) and (2) any modification of the TMPRSS gene, e.g., point mutations, deletions, additions and others with the contemplated phenotype of the swine is less susceptible to an influenza virus and sheds significantly less influenza virus as compared to the non-genetically modified swine.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
the breadth of the claims; the nature of the invention:
The claims are directed to a vast genus of genetically modified swine comprising a genus of modifications of the TMPRSS gene that result in decreased expression of the TMPRSS gene product as compared to the non-genetically modified swine wherein the swine is less susceptible to an influenza virus and sheds significantly less influenza virus as compared to the non-genetically modified swine.
The claims broadly encompass any genetic modifications e.g., genetic modifications by culture, UV light, selective cross breeding, CRISPR and others, wherein the modification may be in somatic cells and not necessarily within the genome of the swine, and wherein the genus of genetic modifications may involve changing a single base pair, deleting an exon, adding a new region of DNA, deleting an intron or deleting the full TMPRSS gene in the TMPRSS gene such that the genetically modified swine exhibits a phenotype characterized by decreased expression of the TMPRSS gene product relative to the non-genetically modified swine. Thus, the claims are directed to a large genus of genetic modifications of the TMPRSS gene in the genome or somatic cells resulting in decreased expression of functional gene products of the at least one modified TMPRSS compared to the non-genetically modified swine.
Claim 12 broadly encompasses a method for making a genetically modified transgenic pig, comprising: knocking out at least one transmembrane protease, serine gene in a pig oocyte. However, the specification describes use of pig zygote to achieve modification of the TMPRSS gene in the genome (para 0019, 0022, 0085, 00165; FIG 5 & 6C).
the amount of direction provided by the inventor; the existence of working examples:
However, the specification does not disclose a reduction to practice of a genetically modified swine comprising a modified TMPRSS gene with decreased gene product other than TMPRSS2 at exon 2. Likewise, the specification does not disclose if swine with other TMPRSS gene modifications, other than knocking out exon 2 of TMPRSS2, would exhibit the phenotype of less susceptibility and shedding significantly less influenza virus compared to non-genetically modified swine. The specification only contemplates the generation of a genetically modified swine (para 0071-0079) and the assortment of TMPRSS genes and corresponding exons that may be targeted to generate KO swine (para 0081-0092). The specification describes that the genetically modified swine may have a resulting phenotype of increased resistance to influenza, as demonstrated by assessment via various experimental assays (para 0091-0097), however the Specification does not exemplify that genetic modification of other TMPRSS genes would result in the desired phenotype. Outside of this scope of enablement, there is no minimal or maximal physiological or phenotypic result which would necessarily tell a skilled artisan the genetically modified swine has developed resistance to influenza.
the state of the prior art; the level of predictability in the art:
The prior art of Whitworth et al (Transgenic Res. 2017; as cited in IDS) teaches a genetically modified transgenic swine comprising a modified Transmembrane protease, serine (TMPRSS) gene, specifically TMPRSS2 with a modified exon 2 causing a knockout phenotype. Whitworth shows predictability for generating the TMPRSS2 exon 2-modified swine (page 6, Birth of live piglets, column 2), and that the swine would have the desired phenotype of less susceptibility and shedding significantly less influenza virus. However, Whitworth does not predict that other TMPRSS genes being knocked out would lead to the desired phenotype.
Moreover, Hatesuer et al (PLOS Pathogens 2013) teach that TMPRSS2 is essential for influenza virus pathogenesis in mice by demonstrating that TMPRSS2 KO mice showed no sign of disease (FIG1A, Results: page 2 column 1). Hatesuer et al disclose that mice were infected with PR8M, A/PuertoRico/8/34 H1N1 and PR8F, A/PuertoRico/8/34 H1N1 (Materials and Methods, page 6, column 1), which are different from the strain used in the instant application (pandemic 2009 H1N1 (pH1N1; CAO4)). Moreover, Hatesuer et al does not teach that its findings in the KO mouse could predict the desired phenotype of less susceptibility and shedding significantly less influenza virus in swine having other TMPRSS knock out, let alone modified. Similarly, Sakai et al (J Virol. 2014) teaches TMPRSS2 is important for in vivo replication of influenza viruses H1N1, H3N2, and H7N9 by demonstrating TMPRSS2 knockout mice showed severe impairment of hemagglutinin protein (HA; cleavage of HA is essential for influenza infectivity) and therefore influenza particles failed to gain infectivity (Abstract: page 1, FIG 4). Moreover, Sakai et al does not teach that findings in the KO mouse could predict the desired phenotype of less susceptibility and shedding significantly less influenza virus in swine having other TMPRSS knock out, let alone modified.
Bertram et al (J Virol. 2010) teaches the TMPRSS2 and TMPRSS4 are essential for cleavage of HA and spread of influenza as shown by using human cell lines subjected to knockdown of TMPRSS2 and TMPRSS4 gene expression. Bertram et al does not teach that its findings in the human in vitro cell culture setting using knockdown approaches could predict in vivo the desired phenotype of less susceptibility and shedding significantly less influenza virus in swine.
Söllner et al (Viruses 2021; as cited in IDS) states that “Despite the enhanced accuracy of CRISPR/Cas tools, there are still risks of off target mutations which could have a negative impact on animal health.” Moreover, Söllner et al states, “depending on the modification, the intrinsic value of dignity of the animal may be compromised or lead to unwanted side effects when altering the immune system”. (Page 12, section 5.3 para 2). Hence, specific genetic modification of other exon or TMPRSS gene, and corresponding phenotype is not necessarily predictable using the describe methods in the specification when used in animals such as swine.
the quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The skilled artisan would be required to perform under levels of experimentation in order to practice the claimed invention. The instant specification does not reduce to practice the claimed invention; the instant specification does not provide guidance on how to reasonably predict which genes and exons should be mutated to gain the desired phenotype of less susceptibility and shedding significantly less influenza virus in the swine. Thus, the skilled artisan would be forced to 1) identify modifications, e.g, point mutations, deletions, additions and others, in the various exons of various TMPRSS genes using various genetic modification methods such as UV light, selective crossbreeding, CRISPR/Cas9 etc., and 2) generate a transgenic swine for each gene modification, determining whether any phenotypic effects were due to how the transgene was mutated, how it is expressed, how it competes with endogenous levels, etc. for the swine to be less susceptible to an influenza virus and sheds significantly less influenza virus as compared to the non-genetically modified swine
the level of one of ordinary skill:
The level of one of ordinary skill is a PhD holder.
Conclusion
When all of the Wands factors are considered together, they establish a prima facie case that the specification is not enabling for the claims. While a lack of a working embodiment cannot be a sole factor in determining enablement, the lack of any working examples, in light of the unpredictable nature of the art and the lack of direction applicants present, provides additional weight to the lack of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have had a reasonable expectation of success in making or using the claimed 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.
Claim 6, 7, 11, 17 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 6 and 11 are indefinite because it is unclear what “modification”/having at least 90% amino acid identity”. As the claims do not recite a wild type amino acid sequence identified by a SEQ ID NO, it is unclear in reference to which amino acid sequence there is least 90% amino acid identity. Different wild-type TMPRSS2 may comprise different amino acid sequences/lengths, and 90% amino acid identity might not be the same in all wild-type TMPRSS2 amino acid sequences.
For the sake of compact prosecution, the recitation of 90% sequence identity in claim 6 is interpreted as disclosed in Figure 6A where knocking out of exon 2 of the TMPRSS2 gene relative to the full length wild TMPRSS2 gene with exon 2 results in a KO pigs having at least 90% amino acid identity corresponding to the wild-type TMPRSS2 gene. Likewise, the recitation of 90% sequence identity in claim 11 is interpreted as disclosed in Figure 6A where knocking out of exon 2 of the TMPRSS2 gene relative to the full length wild TMPRSS2 gene with exon 2 results in a KO pigs having at least 90% amino acid identity corresponding to the wild-type TMPRSS4 gene.
Claim 7 and 17 are indefinite because it is unclear what “effectively impairing” replication of an influenza virus means. The recitation of term “effectively impairing” is a relative term and renders the claim indefinite. The term " impairing " is not defined by the claim. What knocked out conditions are considered "impairing" replication of influenza virus varies widely in the art depending on the TMPRRS2 knocked out gene (homozygous/ heterozygous) as well as the person making the determination. Although it is acknowledged in the specification some TMPRRS2 knocked out gene that are considered by applicant to be " effectively impair replication” (¶ [0025], ¶ [0027] of the published application ), these are merely exemplary and non-limiting. The specification does not disclose the degree to which effective impairment is achieved.
Claim Rejections - 35 USC § 102/103
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 the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 pre-AIA 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.
Alternative-Grounds Rejections
In certain circumstances, claims may be rejected under 35 U.S.C. § 102 and § 103 as alternative grounds. Common scenarios in which §§102/103 rejections are appropriate include:
(1) when the interpretation of the claim(s) is or may be in dispute, i.e., given one interpretation, a rejection under 35 U.S.C. 102 is appropriate and given another interpretation;
(2) when the reference discloses all the limitations of a claim except a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention; see In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980); and
(3) when the reference teaches a product that appears to be the same as, or an obvious variant of, the product set forth in a product-by-process claim although produced by a different process; see In re Thorpe, 777 F.2d 695, 227 USPQ 964 (Fed. Cir. 1985); In re Marosi, 710 F.2d 799, 218 USPQ 289 (Fed. Cir. 1983).
See M.P.E.P. § 706.02(m), Examiner’s Note to form paragraph 7.27. In these situations, if the examiner finds factual grounds for concluding that the prior-art teaching is substantially identical to the claimed invention, she has adequate basis for shifting the burden of proof to applicant to show a material difference. See M.P.E.P. § 2112, part V. In this case, scenario (2) applies to claims 1-4, 6, 7, 12, 13, 14, 15, 16, 17, and scenario (3) applies to claim 20.
Claims 1-4, 6, 7, 12, 13, 15, 14, 16, 17, and 20 are rejected under 35 U.S.C 102(a)(1) as being anticipated by or, in the alternative, under AIA 35 U.S.C. 103(a) as obvious over Whitworth et al 2017 (Whitworth K., Transgenic Res. 2017, Feb;26(1):97-107; as cited in IDS) and Bertram et al 2010 (Bertram S. J Virol. 2010 Oct;84(19):10016-25).
Regarding claim 1, Whitworth teaches a genetically modified transgenic swine comprising a modified Transmembrane protease, serine (TMPRSS) gene, specifically the TMPRSS2 gene, where the modification created a TMPRSS2 biallelic knock-out swine model. Whitworth does not teach expression of functional gene products of the at least one modified TMPRSS gene in the genetically modified transgenic swine is decreased as compared to the non-genetically modified swine, however a biallelic knock-out would inherently produce less functional gene product. On page 2, Whitworth describes in the Materials and Methods section that guide RNAs were designed to be used in pairs to remove the start codon from exon 2 of TMPRSS2 gene. This would inherently reduce expression of functional gene product. For example, translation begins at the start codon, and its removal means the machinery cannot initiate protein synthesis (protein is a gene product) at the correct location, thus cause decreased expression.
Regarding claim 2, Whitworth teaches the genetically modified transgenic swine comprising a modified Transmembrane protease, serine (TMPRSS) gene of claim 1, but does not explicitly teach that the swine is less susceptible to an influenza virus and sheds significantly less influenza virus as compared to the non-genetically modified swine. Whitworth also states (pg 9, Discussion section; pg 2 Introduction), that a TMPRSS2 biallelic knock-out pig should be resistant to various influenza viruses and pigs with a DNA edit in the TMPRSS2 gene for use as a biomedical model of pigs may be resistant to certain types of influenza viruses. Because the structure of the Whitworth’ s transgenic swine is the same as the structure of the modified transgenic swine of claim 1, then any activity resulting from knocking out (KO) at least one Transmembrane protease, serine (TMPRSS) gene is inherently anticipated because the structure of the swine is the same. Therefore, the Whitworth et al., reference teaches each and every limitation of claims 1 and 2, and anticipates claims 1 and 2.
Please, note “When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.” See MPEP 2112.01 or In re Best, 195 USPQ 430, 433 (CCPA 1997). The office does not have the facilities for examining and comparing applicant’s product with the product of the prior art in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the claimed products are functionally different than those taught by the prior art and to establish patentable differences. See Ex parte Phillips, 28 USPQ 1302, 1303 (BPAI 1993), In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray, 10 USPQ2d 1922, 1923 (BPAI 1989).
In the alternative, Bertram et al., discloses that TMPRSS2 is a protease responsible for cleaving influenza hemagglutinin and promoting the spread/shed of influenza (shown by Bertram), therefore it would have been obvious that the reduction in gene product expression of TMPRSS from the genetic modification, would had made the swine of claim 1 less susceptible to an influenza virus and shed significantly less influenza virus as compared to the non-genetically modified swine.
Regarding claim 3, Whitworth teaches a genetically modified transgenic swine comprising a modified Transmembrane protease, serine (TMPRSS) gene, specifically the TMPRSS2 gene.
Regarding claims 4 and 6, Whitworth teaches a genetically modified transgenic swine comprising a modified Transmembrane protease, serine (TMPRSS) gene, specifically the TMPRSS2 gene, wherein exon 2 of TMPRSS2 gene is knock out (page 2, heading of Material and Methods)
Note that for the sake of compact prosecution the recitation of 90% sequence identity in claim 6 is interpreted as disclosed in Figure 6A of the instant application where knocking out of exon 2 of the TMPRSS2 gene relative to the full length wild TMPRSS2 gene with exon 2 results in a KO pigs having at least 90% amino acid identity corresponding to the wild-type TMPRSS2 gene.
Regarding claim 7, Whitworth teaches a genetically modified transgenic swine comprising a modified Transmembrane protease, serine (TMPRSS) gene, specifically the TMPRSS2 gene, wherein exon 2 of TMPRSS2 gene is knock out (page 2, heading of Material and Methods).
Whitworth also states (page 8, Discussion section; pg 2 Introduction), that a TMPRSS2 biallelic knock-out pig should be resistant to various influenza viruses and pigs with a DNA edit in the TMPRSS2 gene for use as a biomedical model of pigs may be resistant to certain types of influenza viruses. Because the structure of the Whitworth’ s transgenic swine is the same as the structure of the modified transgenic swine of claim 1, then any activity resulting from knocking out (KO) at least one Transmembrane protease, serine (TMPRSS) gene is inherently anticipated because the structure of the swine is the same. Therefore, the Whitworth et al., reference teaches each and every limitation of claims 1, and 6-7, and anticipates claims 1 and 6-7.
Please, note “When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.” See MPEP 2112.01 or In re Best, 195 USPQ 430, 433 (CCPA 1997). The office does not have the facilities for examining and comparing applicant’s product with the product of the prior art in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the claimed products are functionally different than those taught by the prior art and to establish patentable differences. See Ex parte Phillips, 28 USPQ 1302, 1303 (BPAI 1993), In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray, 10 USPQ2d 1922, 1923 (BPAI 1989).
In the alternative, Bertram et al., discloses that TMPRSS2 is a protease responsible for cleaving influenza hemagglutinin and promoting the spread/shed of influenza (shown by Bertram), therefore it would have been obvious that the reduction in gene product expression of TMPRSS from the genetic modification, would had made the swine of claim 1 less susceptible to an influenza virus and shed significantly less influenza virus as compared to the non-genetically modified swine.
Regarding claim 12, Whitworth teaches a method for making a genetically modified transgenic pig, comprising: a) knocking out (KO) at least one Transmembrane protease, serine (TMPRSS) gene in a pig oocyte; b) developing the pig oocyte into an embryo; c) transferring said embryo into a surrogate pig; and d) gestating in said surrogate pig said embryo into the genetically modified transgenic pig. Whitworth does not teach expression of functional gene products of the at least one modified TMPRSS gene in the genetically modified transgenic swine is decreased as compared to the non-genetically modified swine, however a biallelic knock-out would inherently produce less functional gene product. On page 2, Whitworth describes in the Materials and Methods section that guide RNAs were designed to be used in pairs to remove the start codon from exon 2 of TMPRSS2 gene. This would inherently reduce expression of functional gene product. For example, translation begins at the start codon, and its removal means the machinery cannot initiate protein synthesis (protein is a gene product) at the correct location, thus cause decreased expression.
Regarding claim 13, Whitworth teaches the method of generating genetically modified transgenic swine comprising a modified Transmembrane protease, serine (TMPRSS) gene of claim 12, but does not explicitly teach that the swine is less susceptible to an influenza virus and sheds significantly less influenza virus as compared to the non-genetically modified swine. Additionally, Whitworth states (page 8, Discussion section; page 2, Introduction), that a TMPRSS2 biallelic knock-out pig should be resistant to various influenza viruses and pigs with a DNA edit in the TMPRSS2 gene for use as a biomedical model of pigs may be resistant to certain types of influenza viruses.
Because the structure of the Whitworth’ s transgenic swine is the same as the structure of the modified transgenic swine of claim 1, then any activity resulting from knocking out (KO) at least one Transmembrane protease, serine (TMPRSS) gene is inherently anticipated because the structure of the swine is the same. Therefore, the Whitworth et al., reference teaches each and every limitation of claims 1 and 2, and anticipates claims 1 and 2.
Please, note “When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.” See MPEP 2112.01 or In re Best, 195 USPQ 430, 433 (CCPA 1997). The office does not have the facilities for examining and comparing applicant’s product with the product of the prior art in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the claimed products are functionally different than those taught by the prior art and to establish patentable differences. See Ex parte Phillips, 28 USPQ 1302, 1303 (BPAI 1993), In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray, 10 USPQ2d 1922, 1923 (BPAI 1989).
In the alternative, Bertram et al., discloses that TMPRSS2 is a protease responsible for cleaving influenza hemagglutinin and promoting the spread/shed of influenza (shown by Bertram), therefore it would have been obvious to one of ordinary skill in the art that the reduction in gene product expression of TMPRSS from the genetic modification, would had made the swine of claim 1 less susceptible to an influenza virus and shed significantly less influenza virus as compared to the non-genetically modified swine.
Regarding claim 14, Whitworth teaches a method for making a genetically modified transgenic pig, comprising: a) knocking out (KO) at least one Transmembrane protease, serine (TMPRSS) gene in a pig oocyte; b) developing the pig oocyte into an embryo; c) transferring said embryo into a surrogate pig; and d) gestating in said surrogate pig said embryo into the genetically modified transgenic pig. Whitworth also teaches the use of CRISPR/Cas9 system to generate the KO (page 3, Materials and Methods). Whitworth does not teach expression of functional gene products of the at least one modified TMPRSS gene in the genetically modified transgenic swine is decreased as compared to the non-genetically modified swine, however a biallelic knock-out would inherently produce less functional gene product. On page 2, Whitworth describes in the Materials and Methods section that guide RNAs were designed to be used in pairs to remove the start codon from exon 2 of TMPRSS2 gene. This would inherently reduce expression of functional gene product. For example, translation begins at the start codon, and its removal means the machinery cannot initiate protein synthesis (protein is a gene product) at the correct location, thus cause decreased expression.
Regarding claim 15, Whitworth teaches a method for making a genetically modified transgenic pig, wherein at least one exon is disrupted and leads to TMPRSS gene KO (page 2, heading of Material and Methods).
Regarding claim 16, Whitworth teaches a method for making a genetically modified transgenic pig, wherein at least one TMPRSS gene is KO, specifically TMPRSS2 (page 2, heading of Material and Methods).
Regarding claim 17, Whitworth teaches the method of creating a knockout TMPRSS2 swine, but does not explicitly teach that there is impaired replication of an influenza virus in a cell of the genetically modified transgenic pig as compared to the non-genetically modified pig. However, Whitworth states (page 8, Discussion section; page 2 Introduction), that a TMPRSS2 biallelic knock-out pig should be resistant to various influenza viruses and pigs with a DNA edit in the TMPRSS2 gene for use as a biomedical model of pigs may be resistant to certain types of influenza viruses. TMPRSS2 is a protease responsible for cleaving influenza hemagglutinin and promoting the spread/shed of influenza (shown by Bertram), therefore it is inherent that due to the reduction in gene product expression of TMPRS2S from the genetic modification, the cells of the swine would have impaired ability to replicate influenza virus.
Regarding claim 20, Whitworth teaches a genetically modified transgenic swine comprising a modified Transmembrane protease, serine (TMPRSS) gene which reads on a genetically modified transgenic pig cell, wherein said genetically modified transgenic pig cell comprises at least one modified Transmembrane protease, serine (TMPRSS) gene, wherein expression of functional gene products of the at least one modified TMPRSS gene in the genetically modified transgenic pig cell is decreased as compared to the non-genetically modified pig cell.
The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.S.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983).
Therefore, the burden of establishing novelty or unobviousness by objective evidence is shifted to applicants. Clear evidence that Whitworth’s swine and method of generating said swine does not possess a critical characteristic that is possessed by the claimed swine or method of making said swine thereof would advance prosecution.
Claim Rejections - 35 USC § 103
Claim interpretation
Claims 8, 9, 10, 18 and 19 recites that the swine of claim 1 comprises a disrupted exon that is any exon other than exon 2, a disrupted Exon 2 and a disrupted Exon 1, or disrupted Exon 2 and a disrupted Exon 3. The transitional term “comprising” or “has” , which is synonymous with “including,” “containing,” or“ characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. (MPEP 2111.03. See, e.g., > Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369,1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (“like the term comprising,’ the terms containing’ and mixture’ are open-ended.”).< Invitrogen Corp. v. Biocrest Mfg., L.P.,327 F.3d 1364, 1368, 66 USPQ2d 1631, 1634 (Fed. Cir. 2003) (“The transition comprising’ in a method claim indicates that the claim is open-ended and allows for additional steps.”); Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d1608, 1613 (Fed. Cir. 1997) “Comprising” is a term of art used in claim language which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim.); Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, 229 USPQ 805 (Fed. Cir. 1986); I n re Baxter, 656 F.2d 679,686, 210 USPQ 795, 803 (CCPA 1981); Ex parte Davis, 80 USPQ 448, 450 (Bd.App. 1948) (“comprising” leaves “the claim open for the inclusion of unspecified ingredients even in major amounts”). As such, the genetically modified transgenic swine are so not limited to include a disrupted exon that is any exon other than exon 2, a disrupted Exon 2 and a disrupted Exon 1, or disrupted Exon 2 and a disrupted Exon 3. The claims are "open" and thus lend themselves to additional exons of the TMPRSS gene that can be modified including a TMPRSS2 knockout animal where exons 2-14 are disrupted.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness. Claims 1, 5, 8, 9, 10, 11, 12, 18, 19 are unpatentable are rejected under 35 U.S.C. 103 as being unpatentable over Whitworth et al 2017 (Whitworth K., Transgenic Res. 2017, Feb;26(1):97-107), Bertram et al 2010 (Bertram S. J Virol. 2010 Oct;84(19):10016-25), and Sakai et al 2014 (Sakai K., J Virol. 2014 May;88(10):5608-16).
Regarding claims 1 and 12, Whitworth et al 2017 anticipates independent claims 1 and 12, as iterated above in the 102 rejection the content of which is incorporated herein, in its entirety.
Whitworth does not teach genetically modified swine transgenic swine with two modified TMPRSS genes.
Regarding claim 5, Bertram teaches that knocking down expression of either TMPRSS2 or TMPRSS4 or both TMPRSS genes in Caco-2 cells markedly reduces the spread the influenza virus demonstrating that these proteases are both responsible for virus release and spread (Figure 5, page 8; column 2, page 6). Moreover, the combination of knocking down TMPRSS2 and TMPRSS4 leads to an even greater reduction in viral release and spread.
It would have been prima fascie obvious to one of ordinary skill in the art prior to the filing of the instant application to use genetic engineering techniques to modify at least two TMPRSS genes such that there is reduction in their functional gene products. One would have been motivated to combine the teachings of Whitworth and Bertram since the combination of knocking down TMPRSS2 and TMPRSS4 leads to an even greater reduction in viral release and spread. Moreover, influenza is known in the art to be a serious concern in the swine industry and human health, thus modifying two TMPRSS genes augments the effect of reduced viral spread. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
Regarding claim 8 (the modified TMPRSS2 gene has a disrupted exon that is any exon other than exon 2 ., 9 (the modified TMPRSS2 gene has a disrupted Exon 2 and a disrupted Exon 1), 10 (the modified TMPRSS2 gene has a disrupted Exon 2 and a disrupted Exon 3), 18 (a disrupted exon that is any exon other than exon 2), and 19 (a disrupted Exon 2 and a disrupted Exon 1, or a disrupted Exon 2 and a disrupted Exon 3), Whitworth does not teach any modifications to exons in the TMPRSS2 gene other than exon 2.
However, Sakai et al teaches a TMPRSS2 knockout mouse where exons 2-14 are disrupted (Figure 2, pg 2.; Materials and methods, pg , Generation of TMPRSS2 KO mice). Sakai et al discloses that in TMPRSS2 KO mice infected with LP influenza A virus (IAVs), cleavage of HA was severely impaired, and consequently, the majority of low-pathogenic (LP) IAV progeny particles failed to gain infectivity, while the viruses were fully activated proteolytically in TMPRSS2+/+ wild-type (WT) mice. Thus, TMPRSS2 KO were highly tolerant of challenge infection by LP IAVs (abstract).
Based on Sakai teachings it would have been prima fascia obvious to one of ordinary skill in the art prior to the filing of the instant application to delete exon 2-14 in order to achieve the result of a disrupted TMPRSS2 gene product. One would be motivated to do so in order to increase the likelihood of modifying the gene enough to cause decreased expression of functional gene product in a swine based on the same gene structure of a knockout mouse for exon 2-14 in the TMPRSS2 gene a reasonable expectation of success.
Regarding claim 11, Whitworth et al., render obvious the limitations of claim 1 including knocking out exon 2 by removing the start codon from exon 2 of TMPRSS2 gene.
Whitworth does not teach a modified TMPRSS4 gene modification having at least 90% amino acid identity corresponding to the wild-type TMPRSS4 gene.
Bertram teaches knocking down expression of TMPRSS4 in Caco-2 cells. Moreover, knocking down TMPRSS4 lead to reduction in viral release and spread, which is similar to a knock down of TMPRSS2 (Figure 5, page 8; column 2, page 6).
Note that the recitation of 90% sequence identity in claim 11 is interpreted as disclosed in Figure 6A where knocking out of exon 2 of the TMPRSS2 gene relative to the full length wild TMPRSS2 gene with exon 2 results in a KO pigs having at least 90% amino acid identity corresponding to the wild-type TMPRSS4 gene.
Based on Bertram teachings it would have been prima fascia obvious to one of ordinary skill in the art prior to the filing of the instant application to use genetic engineering techniques to modify at the TMPRSS4 gene such that there is reduction in functional TMPRSS4 gene products in swine. In relation to the 90% sequence identity to the wild-type TMPRSS4 gene required in claim 11, it would have been obvious to delete based on the teachings of Whitworth et al., and the instant specification where knocking out exon 2 of the TMPRSS2 gene generates a sequence having 90% sequence homology to the full length will type TMPRSS gene.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliana Candelaria whose telephon