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
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.
Election/Restrictions
Applicant’s election without traverse of Invention II, claims 9, 11-14, 16, 30 and 48, in the reply filed on Apr. 8, 2026 is acknowledged.
Claims 1, 3, 9, 11-14, 16, 22, 30, 48-49, 51, 53, 62, 64, 69 and 72-74 remain pending in the current application, claims 1, 3, 22, 49, 51, 53, 62, 64, 69 and 72-74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
The requirement for the restriction of Inventions I-V is still deemed proper and is therefore made FINAL.
Claims 9, 11-14, 16, 30 and 48 have been considered on the merits.
Status of the Claims
Claims 1, 3, 9, 11-14, 16, 22, 30, 48-49, 51, 53, 62, 64, 69 and 72-74 are currently pending.
Claims 1, 3, 22, 49, 51, 53, 62, 64, 69 and 72-74 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 2, 4-8, 10, 15, 17-21, 23-29, 31-47, 50, 52, 54-61, 63, 65-68, 70, and 71 are cancelled.
Claims 9, 11-14, 16, 30 and 48 have been considered on the merits.
Specification
The disclosure is objected to because of the following informalities: the use of trademarks.
The use of the terms BODIPY® in 0053; TexMACS™ in 0282; and X-VIVO® 5 in 0282, which are a trade names or a marks used in commerce, have 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 terms.
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.
Appropriate correction is required.
Claim Objections
The disclosure is objected to because of the following informalities:
Claim 16 is objected to in the recitation of an extra “or” in line 4 in the phase “cancer-associated gene, or snoRNA encoding, miRNA encoding, or lincRNA-encoding gene” and in the interest of improving claim form, it is suggested that the recited phrase be amended to recite “cancer-associated gene, gene, miRNA encoding gene, or lincRNA-encoding gene”.
Appropriate correction is appreciated.
Claim Rejections - 35 USC § 112 (a) 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.
Claims 9, 11-14, 16, 30 and 48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a population of engineered cells which contain an artificially-induced modification in a genomic site where the modification does not affect the expression of more than 100 endogenous genes with a change greater than 10 fold. Thus, the claims are broadly drawn to any engineered cell which contains any possible artificially-induced modification that essentially does not significantly affect the expression of more than 100 endogenous genes. The engineered cell can be from any species and be of any cell type.
The specification only describes a population of human embryonic stem cells (hESCs) with an artificially-induced modification that is a reporter gene expression cassette that is integrated at the genomic sites hSH1 (human safe harbor), hSH3, hSH6, and hSH8 which have few differentially-expressed genes relative to control H9 hESC cultures (Fig. 16 and 0389-0391). The genomic sites are defined as intergenic regions between two genes at particular locations on the chromosomes; hSH1: Fau and ZNHIT2 and chr 11: 65,117,969-65,120,057, hSH3: PIDD1 and RPLP2 and chr 11: 808,403-810,414, hSH6: ANAPC16 and DDIT4 and chr 10: 72,259,705-72,261,554, and hSH8: TEF and TOB2 and chr 17: 64,506,290-64,506,960. There is no description of other genomic sites in other cell types from other species which have this claimed function of where the modification does not affect the expression of more than 100 endogenous genes with a change greater than 10 fold.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claims are broad generics, with respect to all of the potential species of antagonists that may exhibit one, all, of or any of the claimed activity. The possible variations of compounds are limitless with potentially thousands of compounds that may exhibit the claimed activities. The purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed by them. A patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that the inventor invented the claimed invention. Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
The specification lacks sufficient variety of species of cell populations, artificially-induced modifications and genomic sites to reflect this variance in the genera since the specification does not provide any examples of such genera of cell populations, artificially-induced modifications and genomic sites. Accordingly, the specification fails to provide adequate written description for the genera of “a population of engineered cells”, “artificially-induced modification” and “genomic site” and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed had possession of the entire scope of the claimed invention. Moreover, the specification neither describes any of the species by relevant identifying characteristics. Absent of such teachings and guidance as to the structure and function of these particular genera, the specification does not describe the genera in such full, clear, concise and exact terms so as to indicate that Applicant had possession of these genera at the time of filing of the present application. Thus, the written description requirement has not been satisfied.
Claim Rejections - 35 USC § 112 (a) scope of enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9, 11-14, 16, 30 and 48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a population of engineered human embryonic stem cells (hESCs) containing a reporter gene expression cassette integrated at the particular genomic sites, hSHs (human safe harbors): hSH1, hSH3, hSH6, and hSH8, does not reasonably provide enablement for all populations of engineered cells with any artificially-induced modification in a genomic sites where the artificially-induced modification does not affect the expression of more than 100 endogenous genes with a change greater than 10 fold as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, the enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The instant claims are drawn to a population of engineered cells which contain an artificially-induced modification in a genomic site where the modification does not affect the expression of more than 100 endogenous genes with a change greater than 10 fold. Thus, the claims are broadly drawn to include any engineered cell, containing any possible artificially-induced modification that essentially does not significantly affect the expression of more than 100 endogenous genes with a change greater than 10 fold. The engineered cell can be from any species and be of any cell type. The artificially-induced modification includes any modification such as a point mutation or a silent mutation. The genomic site can be anywhere as long as the artificially-induced modification in the genomic site does not affect the expression of more than 100 endogenous genes with a change greater than 10 fold.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The prior art in general teaches the difficultly in establishing safe harbor regions or hotspots in genomes for introducing modifications. For instance, Hillard et al. (Biotechnology and Bioengineering, 2012) reports that at least 30 potential hotspots have been found in CHO cells, but few have been experimentally validated for site-specific integration (pg. 660 Col. 1-2 bridging para.). Hillard teaches hotspots that maximize transcription from a single copy of an integrated transgene are of particular interest for the CHO research community (pg. 660 Col. 2 para. 1). Hillard teaches new hotspots can be systematically identified by studying the CHO epigenome (pg. 660 Col. 2 para. 2). Corteling et al. (US 2023/0227854 A1) reports that:
“there are not enough known and validated ‘safe harbour’ genome loci into which an introduced recombinant gene or genes can be targeted. As noted by Papapetrou and Schambach (Mol Ther. 2016 April; 24(4): 678-684), no fully validated GSHs exist in the human genome. Accordingly, there remains a need to provide transgenic cells and animals that are stable and that provide acceptable expression of the transgene. For transgenic cells with therapeutic utility, the transgenic cell must also be safe, consistent and repeatable, for example across batches.” (0004)
Thus, as the state of the art stands, the engineered cell population with the artificially-induced modification in a genomic site would be unpredictable depending on the specific cell type since the epigenetic landscapes and chromatin structures differ dramatically between different cell types within a species and between species, making it unlikely that the same safe harbor loci would be usable in all cell types from all species. Additionally, the artificially-induced modification and its effects on neighboring genes would be unpredictable, since the epigenetic landscapes and chromatin structures vary among cell types and the type of modification would result in different outcomes on the expression level of endogenous genes.
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification only describes a population of human embryonic stem cells (hESCs) with an artificially-induced modification that is a reporter gene expression cassette that is integrated at the genomic sites hSH1 (human safe harbor), hSH3, hSH6, and hSH8 which have few differentially-expressed genes relative to control H9 hESC cultures (Fig. 16 and 0389-0391). The genomic sites are defined as intergenic regions between two genes at particular locations on the chromosomes; hSH1: Fau and ZNHIT2 and chr 11: 65,117,969-65,120,057, hSH3: PIDD1 and RPLP2 and chr 11: 808,403-810,414, hSH6: ANAPC16 and DDIT4 and chr 10: 72,259,705-72,261,554, and hSH8: TEF and TOB2 and chr 17: 64,506,290-64,506,960. There is no description of other genomic sites in other cell types from other species which have this claimed function of where the modification does not affect the expression of more than 100 endogenous genes with a change greater than 10 fold.
In other words, the specification does not provide any guidance for additional cell types, other genomic sites or other types of artificially-induced modifications. The applicants have provided no additional data demonstrating the claimed engineered cells can include other cell types, other genomic sites or other artificially-induced modifications. The specification only provided specific integration sites have been experimentally tested and shown to work as intended (Example 5) and the claims recite very large genomic regions as transgene integration sites. For example, claim 12 recites the intergenic region between 16 different gene pairs and there is no evidence that all locations within these regions would actually result in consistent transgene expression or allow for an artificially-induced modification and not affect the expression of more than 100 endogenous genes with a change greater than 10 fold.
Therefore, there is no conclusive evidence in the instant disclosure to indicate that the instantly claimed population of engineered cells can include all types of cells, all genomic sites where the artificially-induced modification does not affect the expression of more than 100 endogenous genes with a change greater than 10 fold and all artificially-induced modifications.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to arrive at the claimed invention within the broad scope as instantly claimed.
Claim Rejections - 35 USC § 112 (b)
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 9, 11-14, 16, 30 and 48 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.
In claim 1, line 3-5, the phrase “wherein the artificially-induced modification effects no more than about 10-fold change in expression level of no more than about 100 endogenous genes”, renders the claim and its dependents indefinite, since it is unclear what structure or part of the engineered cell population containing an artificially-induced modification in a genomic site provides this function.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 9, 16, 30 and 48 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Corteling et al. (US 2023/0227854 A1, priority to Aug. 10, 2020).
With respect to claim 9, Corteling teaches a population of engineered cells containing a transgene (artificially-induced modification) in a insertion site (genome site) that is a “safe harbour locus”, which is within the SPATA13 gene on human chromosome 13q12.12 (abstract and 0001). Although, Corteling does not explicitly teach that the artificially-induced modification effects no more than about 10-fold change in expression level of no more than about 100 endogenous genes as recited in claim 9, Corteling teaches, “A small number of sites in the human genome have been proposed to be genomic safe harbors, where transgenes can be inserted and expressed without causing significant alternations in the expression of other genetic elements” (0004). In addition, Corteling teaches that the retroviral insertion in this location does not disrupt any protein coding sequence or any non-coding untranslated sequences (0146). Accordingly, one of ordinary skill in the art would reasonably interpret that the modification in the safe harbor genomic site taught by Corteling which causes little significant changes in the expression of other genetic elements would not affect no more than about 10-fold change in expression level of no more than about 100 endogenous genes.
With respect to claim 16, Corteling teaches integration site is 407,228 bp away from TNFRSF19 (Tumor necrosis factor receptor superfamily member 19 precursor (Toxicity and JNK inducer) (TROY) (Table 2), or the genomic site is at least 1 kb from the nearest cancer associated gene.
With respect to claim 30, Corteling teaches the cells are stem cells, induced pluripotent stem cells, immune cells, T cells, NK cells, or B cells (0023, 0066 and 0069).
With respect to claim 48, Corteling teaches the genomic site is within an intron of the SPATA13 gene, a cancer-associated gene (0013-0014). This site is not AAVS1 or H11.
Therefore, the reference anticipates the claimed subject matter.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
Prosecution Insights