DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants’ reply to the March 19, 2025 Office Action, filed June 19, 2025, is acknowledged. Claims 9-15 remain withdrawn from consideration, as being directed to a non-elected invention. Applicants amend claims 1-3, 5-6, 8, and withdrawn claims 9-15. Claims 1-8 are under examination.
Any rejection of record in the previous office actions not addressed herein is withdrawn. New grounds of rejection are presented herein that were not necessitated by applicant’s amendment of the claims since the office action mailed March 19, 2025. Therefore, this action is not final.
Information Disclosure Statement
The Information Disclosure Statements filed April 8, 2025 and August 14, 2025 have been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of the terms TALEN at page 15, line 2; NANODROP® at page 29, line 27 and page 33, line 12; NUCLEOSPIN® at page 29, line 38 and page 34, line 7; PRIMESTAR® at page 28, line 1; page 29, line 33, page 31, line 12; page 34, line 2; and page 35, line 19; QPIX at page 30, line 18; YEASTAR® at page 27, line 38; page 31, line 10 and page 35, line 17; and BASECLEAR™ at page 27, line 38; page 28, line 25; page 31, line 10; page 32, line 34; and page 35, line 18; which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear 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 Interpretation
The term “non-conventional yeast cell,” although not specifically defined in the specification, is deemed to be a term of art. While the specification does note that Yarrowia cells, and in particular, Yarrowia lipolytica cells are examples of non-conventional yeast cells, the art appears to use the term “non-conventional yeast cell” to include yeast cells other than Saccharomyces cerevisiae as non-conventional. See, e.g., Wagner et al. (89 Fungal Genetics and Biology 126-136 (2016)) that describes non-conventional yeasts that include Hansenula polymorpha, Kluveromyces lactis, Pichia pastoris, and Yarrowia lipolytica.
Claim Objections
Claim 6 is objected to because of the following informalities:
At claim 6, line 4, “NHEJ (non-homologous end joining)” should be changed to “non-homologous end joining (NHEJ).”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
At claim 1, lines 6, and 7, the term “part of” is indefinite because it is unclear how much of the first and/or second at least two double-stranded polynucleotides must have sequence identity with the first and/or second at least two double-stranded polynucleotides.
At claim 1, lines 10-11, the level of sequence identity with the genome of the yeast is not a limitation, so it is unclear how much sequence identity is required.
At claim 1, lines 12-14, the level of sequence identity with the genome of the yeast is not a limitation, so it is unclear how much sequence identity is required.
Claims 2-8 depend from claim 1, and are therefore included in these rejections.
At claim 2, lines 3, 4, and 5, the term “part of” is indefinite because it is unclear how much of the first and/or second at least two double-stranded polynucleotides must have sequence identity with the first and/or second at least two double-stranded polynucleotides.
At claim 2, lines 5-6, the level of sequence identity with the genome of the yeast is not a limitation, so it is unclear how much sequence identity is required.
At claim 2, lines 10-14, the level of sequence identity with the genome of the yeast is not a limitation, so it is unclear how much sequence identity is required.
Claims 3-4 depend from claim 2, and are therefore included in these rejections.
Regarding claim 4, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 7 contains the trademark/trade name TALENs. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe, and, accordingly, the identification/description is indefinite.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 7 recites the broad recitation “a functional genome editing system”, and the claim also recites “optionally TALENs, CRISPR/Cas, CRISPR/Cpf1, or I-SceI” which is the narrower statement of the range/limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 8 recites the broad recitation “a functional heterologous genome editing system”, and the claim also twice recites “optionally a Cas enzyme, optionally Cas9 or Cas9 nickase; Cpf1; I-Sce1” which are the narrower statements of the range/limitation. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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 6 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.
Claim 6 recites that the non-conventional yeast cell optionally is deficient in an NHEJ (non-homologous end joining) component. Because the NHEJ is an optional limitation, claim 6 is deemed to not further limit claim 1 from which claim 6 depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 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.
Claims 1-8 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Roubos et al. (PCT Patent Application Publication No. WO 2018/127611, published July 12, 2018, filed April 4, 2018, and claiming priority to European Patent Application No. 17165201.9, filed April 6, 2017, and cited in the Information Disclosure Statement filed August 14, 2025, see the entire document). This rejection is modified as necessitated by Applicants’ amendments and maintained.
The applied reference has a common inventor and assignee 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.
Regarding claim 1, Roubos discloses a self- guiding integration construct for a genome editing system (abstract). Roubos discloses that the self-guiding integration construct (SGIC) is a donor polynucleotide for CRISPR/Cas gene editing, and which contains a guide-RNA expression cassette (page 17, lines 13-25). Roubos discloses that SGIC comprising guide-RNA expression cassette and that the donor polynucleotide part is flanked at its 5'-terminus by a first polynucleotide and at its 3'-terminus by a second polynucleotide, and that the first and second polynucleotide have sequence identity with sequences flanking the target sequence in the target genome (page 17, line 37 to page 18, lines 1-3).
Roubos discloses that the gene editing composition comprising two or more polynucleotide members that have sequence identity with each other which allows them to recombine in vivo in a host cell, to yield a self-guiding integration construct (page 27, lines 5-7). Roubos discloses that the two double-stranded oligonucleotide molecules have sequence identity wherein a first double-stranded molecule has a part that has sequence identity with a sequence in the genome that is located 5' of the target sequence and a second double stranded oligonucleotide has a part that has sequence identity with a sequence in the genome that is located 3' of the target sequence (page 23, lines 5-18). Roubos discloses that the self-guiding integration construct is integrated into the genome at the site where the first and second polynucleotide have sequence identity with the sequences flanking the target sequence in the target genome in the host cell wherein the site is located immediately adjacent to the induced double-stranded break or single-stranded break (page 26, lines 10-18). Roubos discloses that the yeast cell can be a Kluveromyces lactis cell, a Yarrowia lipolytica cell, a Hansenula polymorpha cell, a Pichia pastoris cell, or an Issatchenkia orientalis cell, which yeast cells are considered non-conventional yeast cells (page 42, lines 25-32).
Regarding claims 2-3, Roubos discloses that the gene editing composition comprising two or more polynucleotide members, which is interpreted as at least two, or any number more than two, including three or four or more, with the polynucleotide members having sequence identity with each other which allows them to recombine in vivo in a host cell to yield a single self-guiding integration construct (page 19, lines 4-34). Roubos further discloses that a first of the two or more polynucleotide members has a part that has sequence identity with a part of a second of the two or more polynucleotide members and that such that a self -guiding integration construct as disclosed herein can be assembled within a cell (page 19, lines 4-34).
Regarding claim 4, Roubos teaches that the polynucleotide expression construct comprises the components comprising a promoter, a coding sequence and a terminator (page 20, lines 3-8).
Regarding claim 5, Roubos discloses that the gene editing system can be used to create library of self-guiding integration constructs (i.e., polynucleotide constructs) where additional functional or non-functional polynucleotide elements are present on the constructs and are linked to the guide RNAs (page 17, lines 17-31). Roubos discloses that the part of the self- guiding integration construct comprising the guide-RNA expression cassette and the donor polynucleotide part is flanked at its 5'-terminus by a first polynucleotide and at its 3'-terminus by a second polynucleotide and that the first and second polynucleotide have sequence identity with sequences flanking the target sequence in the target genome (i.e., the construct is assembled from two polynucleotides) (page 17, line 4 to page 18. Line 3). Roubos discloses that the host cell population comprises a library of self-guiding integration constructs and preferably comprising 2, 3, 4, 5, 6, 7, 8, 9, 10 or more constructs (page 26, lines 1-3).
Regarding claim 6, Roubos teaches that the host cell is a eukaryotic cell, preferably a fungal cell or a yeast cell or a filamentous fungus cell and wherein the eukaryotic cell is deficient in an NHEJ (non-homologous end joining) component (page 42, lines 14-24).
Regarding claims 7-8, Roubos discloses that the genome editing system can be CRISPR/Cas9 or CRISPR/Cpf1, and can be a nickase (page 20, lines 30-36).
Roubos discloses each and every limitation of claims 1-8, and therefore Roubos anticipates claims 1-8.
Claims 1-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Verwaal et al. (PCT Patent Application Publication No. WO 2016/110512, published July 14, 2016, filed January 6, 2016, and cited in the Information Disclosure Statement filed November 2, 2021). This rejection is modified as necessitated by Applicants’ amendments and maintained.
Regarding claim 1, Verwaal discloses a CRISPR-Cas system for a yeast host cell (abstract). Verwaal discloses a multiplex CRISPR-Cas system gene editing system wherein multiple donor polynucleotides are used (page 20, lines 23-34). Verwaal discloses that the donor polynucleotides are also referred as exogenous polynucleotides can be double-stranded molecules comprising one or more distinct exogenous polynucleotides that encode different or identical expression products while a part of the exogenous polynucleotides has sequence identity to a part of the target-polynucleotide (page 30, line 25 to page 31, line 2). Verwaal discloses that the gene editing composition comprises at least two distinct exogenous polynucleotides having sequence identity with each other such that recombination of the distinct exogenous polynucleotides is facilitated, wherein the recombination preferably is in vivo recombination in the host cell (page. 31, lines 7-24). Verwaal discloses that additional polynucleotides comprise sequence identity with only the exogenous polynucleotides such that a complex of these can be formed and that the formed construct comprising the complex of exogenous polynucleotides can be introduced into the target polynucleotide (page 31, line 30 to 32 line 2). Verwaal discloses that the exogenous polynucleotides can be present in a vector (i.e., as a formed construct), can have sequence identity to a part of the target-polynucleotide upstream of the PAM associated with the guide-sequence, and has a sequence identity to a part of the target polynucleotide downstream of the PAM (i.e., at the 3'-end) (page 32, lines 3-9). Verwaal teaches that the donor polypeptides can be derived from various sources and are also referred as expression cassettes, can be integrated into the genomic DNA in the host cell (pg. 106, lines 3-7). Verwaal discloses that the yeast cell can be a Kluveromyces lactis cell, a Yarrowia lipolytica cell, a Hansenula polymorpha cell, a Pichia pastoris cell, or an Issatchenkia orientalis cell, which yeast cells are considered non-conventional yeast cells (page 59, line 32 to page 60, line 5).
Regarding claims 2-3, Verwaal discloses a multiplex CRISPR-Cas system gene editing system wherein multiple donor polynucleotides are used (page 20, lines 29-35) can be used in gene editing of a target gene using CRISPR-Cas system and three expression cassettes (page 115, lines 20-22). Verwaal discloses that three donor DNA expression cassettes such as crtE, crtl and crtYB are transformed in a subsequent transformation together with 100 base pair flank sequences that target the expression cassettes to the desired locations in vivo in genomic DNA (page 115, lines 26-29). Verwaal further discloses that the CRISPR-Cas system preferably comprises two or more exogenous polynucleotides and guide polynucleotides enabling the formation of two or more CRISPR-Cas complexes wherein the system can conveniently be used to modulate expression of two or more target-polynucleotides to target multiple genomic sites in the host cell (page 45, lines 10-17).
Regarding claim 4, Verwaal discloses that a series of polynucleotides, or gene clusters encode a biological compound comprising a biomass or a biopolymer or a metabolite, composing a biosynthetic or metabolic pathway (page 52, lines 7-17).
Regarding claim 5, Verwaal discloses that the multiplex CRISPR-Cas gene editing method can be used for polynucleotide library insertion into the genome of a host cell (page 20, lines 30-32). Verwaal discloses that the CRISPR-Cas system comprises exogenous polynucleotide or donor polynucleotide and enables synthesis of two or more of combination polynucleotides and library synthesis of such combination polynucleotides (page 45, lines 25-29). Verwaal also teaches that such library can be provided as a pool and be used to make a library of vectors and/or polynucleotides (page 45, lines 25-29).
Regarding claim 6, Verwaal discloses that the polynucleotide sequence targeting the host genome at the PAM or at the proximity of the break wherein the host cell is a eukaryote or preferably a yeast and wherein the host cell is deficient in a component associated with NHEJ (page 49, line 34 to page 50, line 8).
Regarding claims 7-8, Verwaal discloses that the method provides a composition comprising CRISPR-Cas system that is used for introduction of donor polynucleotide or polynucleotide library insertion into the genome of a host cell (page 20, lines 29-32). Verwaal discloses that the Cas enzyme can be Cas9 (page 36, lines 30-31).
Verwaal discloses each and every limitation of claims 1-8, and therefore Verwaal anticipates claims 1-8.
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.
Claims 1, 6, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, and 9-10 of U.S. Patent No. 10,590,436 in view of Verwaal et al. (PCT Patent Application Publication No. WO 2016/110512, published July 14, 2016, filed January 6, 2016, and cited in the Information Disclosure Statement filed November 2, 2021). This rejection is modified as necessitated by Applicants’ amendments and maintained.
Regarding claim 1 of the instant application, claims 1, 5 and 9-10 of the ‘436 patent claim a gene-editing composition comprising CRISPR-Cas system wherein the polynucleotides encoding Cas and guide RNA are comprised in a vector that comprises at least two distinct polynucleotides having sequence identity with each other. Claims 1, 5 and 9-10 of the U’436 patent claim that the composition of CRISPR-Cas system comprises distinct exogenous polynucleotides that upon cleavage of the target-polynucleotide by the CRISPR-Cas complex recombine with the target-polynucleotide, resulting in a modified target-polynucleotide wherein the two distinct exogenous polynucleotides comprise sequence identity with each other such that recombination of the distinct exogenous polynucleotides is facilitated, wherein the recombination is in vivo recombination in the host cell. The ‘436 patent claims that the yeast is a Yarrowia lipolytica yeast, which is a non-conventional yeast.
The ’436 patent does not claim that the double-stranded polynucleotide construct having at a 5'-end thereof sequence identity with a genome of the cell within proximity of a break in the genome of the cell and wherein the double-stranded polynucleotide construct has at a 3'-end thereof sequence identity with a genome of the cell within proximity of a break in the genome of the cell, and wherein the double-stranded polynucleotide construct integrates into the genome of the cell within the proximity of the break in the genome of the cell (claim 1).
Regarding claim 1, Verwaal discloses a CRISPR-Cas system for a yeast host cell (abstract). Verwaal discloses a multiplex CRISPR-Cas system gene editing system wherein multiple donor polynucleotides are used (page 20, lines 23-34). Verwaal discloses that the donor polynucleotides are also referred as exogenous polynucleotides can be double-stranded molecules comprising one or more distinct exogenous polynucleotides that encode different or identical expression products while a part of the exogenous polynucleotides has sequence identity to a part of the target-polynucleotide (page 30, line 25 to page 31, line 2). Verwaal discloses that the gene editing composition comprises at least two distinct exogenous polynucleotides having sequence identity with each other such that recombination of the distinct exogenous polynucleotides is facilitated, wherein the recombination preferably is in vivo recombination in the host cell (page. 31, lines 7-24). Verwaal discloses that additional polynucleotides comprise sequence identity with only the exogenous polynucleotides such that a complex of these can be formed and that the formed construct comprising the complex of exogenous polynucleotides can be introduced into the target polynucleotide (page 31, line 30 to 32 line 2). Verwaal discloses that the exogenous polynucleotides can be present in a vector (i.e., as a formed construct), can have sequence identity to a part of the target-polynucleotide upstream of the PAM associated with the guide-sequence, and has a sequence identity to a part of the target polynucleotide downstream of the PAM (i.e., at the 3'-end) (page 32, lines 3-9). Verwaal teaches that the donor polypeptides can be derived from various sources and are also referred as expression cassettes, can be integrated into the genomic DNA in the host cell (pg. 106, lines 3-7). Verwaal discloses that the yeast cell can be a Kluveromyces lactis cell, a Yarrowia lipolytica cell, a Hansenula polymorpha cell, a Pichia pastoris cell, or an Issatchenkia orientalis cell, which yeast cells are considered non-conventional yeast cells (page 59, line 32 to page 60, line 5).
Regarding claim 6, Verwaal discloses that the polynucleotide sequence targeting the host genome at the PAM or at the proximity of the break wherein the host cell is a eukaryote or preferably a yeast and wherein the host cell is deficient in a component associated with NHEJ (page 49, line 34 to page 50, line 8).
Regarding claim 7, Verwaal discloses that the method provides a composition comprising CRISPR-Cas system that is used for introduction of donor polynucleotide or polynucleotide library insertion into the genome of a host cell (page 20, lines 29-32). Verwaal discloses that the Cas enzyme can be Cas9 (page 36, lines 30-31).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘436 patent with the disclosure of Verwaal because Verwaal is directed to genome editing in non-conventional yeast (Yarrowia lipolytica). As such, one of ordinary skill in the art would be motivated to provide multiple gene constructs in order to target multiple sites within the yeast cell in order to provide yeast cells to produce one or more desired polypeptides for use in treatment of diseases.
Claims 1, 6, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of U.S. Patent No. 10,619,170 in view of Verwaal et al. (PCT Patent Application Publication No. WO 2016/110512, published July 14, 2016, filed January 6, 2016, and cited in the Information Disclosure Statement filed November 2, 2021). This rejection is modified as necessitated by Applicants’ amendments and maintained.
Regarding claim 1 of the instant application, claims 1 and 9 of the ‘170 patent claim a gene-editing composition comprising CRISPR- Cas system wherein first and second polynucleotide encoding each guide- polynucleotide has sequence identity with a vector, and wherein each guide- polynucleotide-encoding polynucleotide has sequence identity with each other. Claims 1 and 9 of the ‘170 patent claim that the composition of CRISPR-Cas system comprises distinct exogenous polynucleotides that upon cleavage of the target-polynucleotide by the CRISPR-Cas complex recombine with the target-polynucleotide, resulting in a modified target-polynucleotide wherein the two distinct exogenous polynucleotides comprise sequence identity with each other such that recombination of the distinct exogenous polynucleotides is facilitated, wherein the recombination is in vivo recombination in the host cell.
The ’170 patent does not claim that the double-stranded polynucleotide construct having at a 5'-end thereof sequence identity with a genome of the cell within proximity of a break in the genome of the cell and wherein the double-stranded polynucleotide construct has at a 3'-end thereof sequence identity with a genome of the cell within proximity of a break in the genome of the cell, and wherein the double-stranded polynucleotide construct integrates into the genome of the cell within the proximity of the break in the genome of the cell (claim 1). The ‘170 patent does not claim that the eukaryotic host cell that is deficient in an NHEJ component.
Regarding claim 1, Verwaal discloses a CRISPR-Cas system for a yeast host cell (abstract). Verwaal discloses a multiplex CRISPR-Cas system gene editing system wherein multiple donor polynucleotides are used (page 20, lines 23-34). Verwaal discloses that the donor polynucleotides are also referred as exogenous polynucleotides can be double-stranded molecules comprising one or more distinct exogenous polynucleotides that encode different or identical expression products while a part of the exogenous polynucleotides has sequence identity to a part of the target-polynucleotide (page 30, line 25 to page 31, line 2). Verwaal discloses that the gene editing composition comprises at least two distinct exogenous polynucleotides having sequence identity with each other such that recombination of the distinct exogenous polynucleotides is facilitated, wherein the recombination preferably is in vivo recombination in the host cell (page. 31, lines 7-24). Verwaal discloses that additional polynucleotides comprise sequence identity with only the exogenous polynucleotides such that a complex of these can be formed and that the formed construct comprising the complex of exogenous polynucleotides can be introduced into the target polynucleotide (page 31, line 30 to 32 line 2). Verwaal discloses that the exogenous polynucleotides can be present in a vector (i.e., as a formed construct), can have sequence identity to a part of the target-polynucleotide upstream of the PAM associated with the guide-sequence, and has a sequence identity to a part of the target polynucleotide downstream of the PAM (i.e., at the 3'-end) (page 32, lines 3-9). Verwaal teaches that the donor polypeptides can be derived from various sources and are also referred as expression cassettes, can be integrated into the genomic DNA in the host cell (pg. 106, lines 3-7). Verwaal discloses that the yeast cell can be a Kluveromyces lactis cell, a Yarrowia lipolytica cell, a Hansenula polymorpha cell, a Pichia pastoris cell, or an Issatchenkia orientalis cell, which yeast cells are considered non-conventional yeast cells (page 59, line 32 to page 60, line 5).
Regarding claim 6, Verwaal discloses that the polynucleotide sequence targeting the host genome at the PAM or at the proximity of the break wherein the host cell is a eukaryote or preferably a yeast and wherein the host cell is deficient in a component associated with NHEJ (page 49, line 34 to page 50, line 8).
Regarding claim 7, Verwaal discloses that the method provides a composition comprising CRISPR-Cas system that is used for introduction of donor polynucleotide or polynucleotide library insertion into the genome of a host cell (page 20, lines 29-32). Verwaal discloses that the Cas enzyme can be Cas9 (page 36, lines 30-31).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘436 patent with the disclosure of Verwaal because Verwaal is directed to genome editing in non-conventional yeast (Yarrowia lipolytica). As such, one of ordinary skill in the art would be motivated to provide multiple gene constructs in order to target multiple sites within the yeast cell in order to provide yeast cells to produce one or more desired polypeptides for use in treatment of diseases.
Claims 1-3 and 6-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 7-9 of U.S. Patent No. 11,149,268 in view of Verwaal et al. (PCT Patent Application Publication No. WO 2016/110512, published July 14, 2016, filed January 6, 2016, and cited in the Information Disclosure Statement filed November 2, 2021). This rejection is modified as necessitated by Applicants’ amendments and maintained.
Regarding claim 1, claims 1 and 4 of the ‘268 patent claim a method for assembly within a cell of at least two double-stranded nucleic acid molecules into a single double-stranded nucleic acid construct. The ‘268 patent claims that a first of the at least two double-stranded nucleic acid molecules integrates into a second of the at least two double stranded nucleic acid molecules to result into a single double-stranded nucleic acid construct, wherein a part of the first single-stranded oligonucleotide has sequence identity with the first of the at least two double-stranded nucleic acid molecules and wherein a part of the first single-stranded oligonucleotide has sequence identity with the second of the at least two double-stranded nucleic acid molecules, wherein the sequence identity is sufficient for assembly of the
double-stranded nucleic acid construct, said method comprising contacting the cell with the single-stranded oligonucleotides and at least one of the double- stranded nucleic acid molecules such that the single-stranded oligonucleotides and at least one of the double-stranded nucleic acid molecules are introduced into the cell and wherein the second of the at least two double-stranded nucleic acid molecules is a genome locus. The ‘268 patent claims 1 that integration occurs within proximity of a break in the second of the at least two double-stranded nucleic acid molecules.
Regarding claims 2-3, the ‘268 patent claims that the method is a multiplex method of assembly within a cell of multiple double-stranded nucleic acid molecules assembled into single or multiple double-stranded nucleic acid constructs.
Regarding claim 6, the ‘268 patent claims that the cell is a eukaryotic cell, optionally a fungus (yeast or filamentous fungus) and/or wherein the cell is deficient in an NHEJ (non-homologous end joining) component.
Regarding claims 7-8, the ‘268 patent claims limitations requiring that the break is induced by a functional genome editing system, comprising CRISPR/Cas, and wherein the cell expresses a functional heterologous genome editing enzyme, optionally a Cas enzyme, optionally Cas9.
The ‘268 patent fails to claim that the cell is a non-conventional yeast.
Regarding claim 1, Verwaal discloses a CRISPR-Cas system for a yeast host cell (abstract). Verwaal discloses a multiplex CRISPR-Cas system gene editing system wherein multiple donor polynucleotides are used (page 20, lines 23-34). Verwaal discloses that the donor polynucleotides are also referred as exogenous polynucleotides can be double-stranded molecules comprising one or more distinct exogenous polynucleotides that encode different or identical expression products while a part of the exogenous polynucleotides has sequence identity to a part of the target-polynucleotide (page 30, line 25 to page 31, line 2). Verwaal discloses that the gene editing composition comprises at least two distinct exogenous polynucleotides having sequence identity with each other such that recombination of the distinct exogenous polynucleotides is facilitated, wherein the recombination preferably is in vivo recombination in the host cell (page. 31, lines 7-24). Verwaal discloses that additional polynucleotides comprise sequence identity with only the exogenous polynucleotides such that a complex of these can be formed and that the formed construct comprising the complex of exogenous polynucleotides can be introduced into the target polynucleotide (page 31, line 30 to 32 line 2). Verwaal discloses that the exogenous polynucleotides can be present in a vector (i.e., as a formed construct), can have sequence identity to a part of the target-polynucleotide upstream of the PAM associated with the guide-sequence, and has a sequence identity to a part of the target polynucleotide downstream of the PAM (i.e., at the 3'-end) (page 32, lines 3-9). Verwaal teaches that the donor polypeptides can be derived from various sources and are also referred as expression cassettes, can be integrated into the genomic DNA in the host cell (pg. 106, lines 3-7). Verwaal discloses that the yeast cell can be a Kluveromyces lactis cell, a Yarrowia lipolytica cell, a Hansenula polymorpha cell, a Pichia pastoris cell, or an Issatchenkia orientalis cell, which yeast cells are considered non-conventional yeast cells (page 59, line 32 to page 60, line 5).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute Verwaal’s non-conventional yeasts for the yeast or fungal cells of the ‘268 patent because, as known in the art, each of these cell types can be genetically modified by gene editing systems, including CRISPR systems. As such, one of ordinary skill in the art would have had a predictable and reasonable expectation of success in using any well-known cell system in order to provide a genetically modified organism, which can be used to produce a variety of therapeutic products.
Response to Arguments
Regarding the rejections under 35 U.S.C. §§ 102(a)(1) and 102(a)(2) over Verwaal and Roubos, respectively, Applicants’ arguments have been fully considered but are not deemed to be persuasive.
Applicants assert that neither Verwaal nor Roubos discloses a method for genome editing in non-conventional yeast.
However, although the examples of each patent application publication are directed to Saccharomyces cerevisiae (a conventional yeast), each of Verwaal and Roubos disclose that a wide variety of yeast cells (as well and filamentous fungal cell) can be used for CRISPR/Cas genome editing. In particular, each of Verwaal and Roubos disclose that the yeast cell can be a Kluveromyces lactis cell, a Yarrowia lipolytica cell, a Hansenula polymorpha cell, a Pichia pastoris cell, or an Issatchenkia orientalis cell. Each of these yeast cells are considered to be non-conventional yeast cells (see, e.g., Wagner et al. (89 Fungal Genetics and Biology 126-136 (2016)) that describes non-conventional yeasts that include Hansenula polymorpha, Kluveromyces lactis, Pichia pastoris, and Yarrowia lipolytica. Therefore, Applicants’ arguments are not persuasive because each of Verwaal and Roubos are deemed to anticipate the claimed invention, as amended to require that the yeast cells are non-conventional yeast cells. Therefore, these rejections are modified as necessitated by Applicants’ amendments, and maintained.
Regarding the non-statutory double patenting rejections over U.S. Patent Nos. 10,590,436; 10,619,170; and 11,149,268; Applicants’ arguments have been fully considered, but are not deemed to be persuasive.
As with the rejections under 35 U.S.C. §§ 102(a)(1) and 102(a)(2) above, Applicants assert that the amendment to require that the yeast cells are non-conventional yeast cells.
However, it is noted that Verwaal does disclose that the yeast cells can be non-conventional yeasts, including a Kluveromyces lactis cell, a Yarrowia lipolytica cell, a Hansenula polymorpha cell, a Pichia pastoris cell, or an Issatchenkia orientalis cell.
As noted above, these rejections are modified as necessitated by Applicants’ amendments, and maintained.
Regarding the non-statutory double patenting rejection over U.S. Patent Nos. 11,396,665, and 11,466,269, it is noted that the ‘665 patent is directed to genome editing in filamentous fungal cells and the ‘269 patent is directed to genome editing in algal cells, rather than yeast cells (conventional or non-conventional). Therefore, these rejections are withdrawn.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wagner et al. (89 Fungal Genetics and Biology 126-136 (2016)) describes non-conventional yeasts that include Hansenula polymorpha, Kluveromyces lactis, Pichia pastoris, and Yarrowia lipolytica (abstract).
Löbs et al. (2 Synthetic and Systems Biotechnology 198-207 (2017) describe genome and metabolic engineering in non-conventional yeasts (abstract). Löbs discloses that non-conventional yeasts include, among others, Hansenula polymorpha, Kluveromyces lactis, Pichia pastoris, and Yarrowia lipolytica (abstract).
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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