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 .
Claim Status
Claims 1-5, 7, 9-11, 13, 15, 36, 38-39, 42-44 and 58 are pending.
Claims 5, 7, 9-11 and 13 are withdrawn.
Claims 1-4, 15, 36, 38-39, 42-44 and 58 are under examination.
Election/Restrictions
Applicant’s election without traverse of the following invention
Invention
Group I claims 1-5, 7, 9-11, 13, 15, 36, 38-39 and 42-44, and 58 drawn to a to a composition comprising two or more of (a), (b), (c), and (d): (a) one or both of (1) and (2): (1) one or more compounds that disrupt expression or activity of transforming growth factor (TGF)-beta receptor 2 (TGFBR2); (2) natural killer (NK) cells comprising a disruption of expression or activity of TGFBR2 endogenous to the NK cells; (b) one or both of (1) and (2): (1) one or more compounds that disrupt expression or activity of glucocorticoid receptor (GR); (2) natural killer (NK) cells comprising a disruption of expression or activity of GR endogenous to the NK cells; (c) one or more integrin inhibitors; and (d) one or more TGF-beta inhibitors, wherein the two or more of (a), (b), (c), and (d) may or may not be in the same formulation and a kit comprising the composition and/or one or more reagents to generate the compositions, housed in a suitable container
in the reply filed on 27th, June, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s election without traverse of the following species
Species
(a)(1) and/or (a)(2) and (b)(1) and/or (b)(2) which includes:
(a)(1) one or more compounds that disrupt expression or activity of transforming
growth factor (TGF)-beta receptor 2 (TGFBR2); and/or
(a)(2)natural killer (NK) cells comprising a disruption of expression or activity of
TGFBR2 endogenous to the NK cells
And
(b)(1) one or more compounds that disrupt expression or activity of glucocorticoid
receptor (GR); and/or
(b)(2) natural killer (NK) cells comprising a disruption of expression or activity of GR
endogenous to the NK cells
(the elected species reads on claims 1, 2-4, 15, 36, 38-39, 42-43)
in the reply filed on 27th, June, 2025 is acknowledged. Claims 1-4, 15, 36, 38-39, 42-44 and 58 encompass the elected species.
The requirement is still deemed proper and is therefore made FINAL.
Claims 5, 7, 9-11 and 13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Objections to Specification
Browser Executable Code
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (“www” para. [0221] and https:// para. [0205]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
This objection would be overcome if the embedded hyperlink and/or other form of browser-executable code is removed, or the reference to the website is amended to be limited to the top-level domain name.
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 1-4, 15, 36, 38-39, 42-44 and 58 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 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.
The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include a disclosure of a representative number of species to describe the complete structure of the claimed genus and/or disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
Breadth of the Claims
Instant claims encompass the genera:
(a)(1) “one or more compounds that disrupt expression or activity of transforming growth factor (TGF)-beta receptor 2 (TGFBR2)”
This broadest reasonable interpretation of the scope of this genus includes all compounds of all possible structure that disrupt expression or activity of TGFBR2 in all possible ways. This includes changes or disruptions to all possible compounds that interact in any way with the TGFBR2 pathway and therefore affect its expression or activity, including structurally and functionally distinct embodiments such as but not necessarily limited to small molecules, proteins, peptides, and viral and non-viral vectors. This genus also includes structurally and functionally distinct nucleic acids such as but not necessarily limited to gRNAs, siRNAs, shRNAs, mRNAs, and anti-sense oligonucleotides. The breadth of this genus therefore also encompasses yet-undiscovered compounds that have the downstream effect of changing expression of activity of TGFBR2 cells in any way, including upregulation or downregulation. This encompasses an unfathomable number of structurally and functionally distinct compounds.
Regarding the breadth of (a)(1), Applicant is directed to the art of Itatani et al. (Int J Mol Sci
. 2019 Nov 20;20(23):5822.;henceforth “Itatani”). Itatani evidences an exemplary TGFβ pathway (see Figure 1 copied below).
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Applicant’s claim (a)(1) encompasses all possible all possible compounds that interact in any way with all possible components of aTGFBR2 pathway, such as above and other related pathways that therefore affect its expression or activity.
(a)(2) “natural killer (NK) cells comprising a disruption of expression or activity of TGFBR2 endogenous to the NK cells”
This encompasses NK cells that have a disruption of expression or activity of TGFBR2 in all possible ways including disruption of all possible pathways that interact in any way with the TGFBR2 pathway and therefore affect its expression or activity. The breadth of this genus therefore encompasses yet-undiscovered disruptions that have the downstream effect of changing expression of activity of TGFBR2 in NK cells in any way, including upregulation or downregulation. This encompasses an unfathomable number of structurally and functionally distinct disruptions in NK cells.
(b)(1) “one or more compounds that disrupt expression or activity of glucocorticoid receptor (GR)”
This broadest reasonable interpretation of the scope of this genus includes all compounds of all possible structure that disrupt expression or activity of GR in all possible ways. This includes changes or disruptions to all possible compounds that interact in any way with the GR pathway and therefore affect its expression or activity, including structurally and functionally distinct embodiments such as but not necessarily limited to small molecules, proteins, peptides, and viral and non-viral vectors. This genus also includes structurally and functionally distinct nucleic acids such as but not necessarily limited to gRNAs, siRNAs, shRNAs, mRNAs, and anti-sense oligonucleotides. The breadth of this genus therefore also encompasses yet-undiscovered compounds that have the downstream effect of changing expression of activity of GR in any way, including upregulation or downregulation. This encompasses an unfathomable number of structurally and functionally distinct compounds.
Regarding the breadth of (b)(1), Applicant is directed to the art of Smoak et al. (Mech Ageing Dev. 2004 Oct-Nov;125(10-11):697-706.; henceforth “Smoak”). Smoak evidences and exemplary GR pathway (see, for example, Figure 4; copied below).
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Applicant’s claim (b)(1) encompasses all possible all possible compounds that interact in any way with all possible components of a GR pathway, such as above and other related pathways that therefore affect its expression or activity.
(b)(2) “natural killer (NK) cells comprising a disruption of expression or activity of GR endogenous to the NK cells”
This encompasses NK cells that have a disruption of expression or activity of GR in all possible ways including disruption of all possible pathways that interact in any way with the GR pathway and therefore affect its expression or activity. The breadth of this genus therefore encompasses yet-undiscovered disruptions that have the downstream effect of changing expression of activity of GR in NK cells in any way, including upregulation or downregulation. This encompasses an unfathomable number of structurally and functionally distinct disruptions in NK cells.
Disclosure of Structure and Disclosure of Species
Regarding the compounds of (a)(1), Applicant generally discloses the sub-genera of TGF-β inhibitors (para. [0107-0108]) or TGF-β pathway inhibitors (para. [0108]). Applicant specifically discloses the nucleic acid Trabedersen (para. [0108]). Applicant specifically discloses 11 gRNA sequences that target TGFBR2 (SEQ ID NO: 17-18; Table 2 para. [0020]), and SEQ ID NO:1-9 which are gRNAs that target TGF-beta R2 gene by CRISPR gene editing (para. [0041]; Figures 25A-B).
Regarding the disruptions of (a)(2), Applicant generally discloses the vast sub-genera of genetic disruptions of insertions, frameshift and missense mutations, deletions, knock-in, and knock-out of the gene or part of the gene, including deletions of the entire gene caused by the vast sub-genera of
Gene-editing (para. [0050]). Applicant specifically discloses a disruption by blocking TGF-β signalling one set of NK cells with galunisertib. Applicant specifically discloses 11 gRNA sequences that target TGFBR2 (SEQ ID NO: 17-18; Table 2 para. [0020] and SEQ ID NO:1-9) and make the disruption of deletion of the gene in NK cells (Example 13)
Regarding the compounds of (b)(1), although Applicant discloses a knockout made by CRISPR in the GR, specific gRNA sequences do not appear to be disclosed.
Regarding the disruptions of (b)(2), Applicant generally discloses the vast sub-genera of genetic disruptions of insertions, frameshift and missense mutations, deletions, knock-in, and knock-out of the gene or part of the gene, including deletions of the entire gene caused by the vast sub-genera of
Gene-editing (para. [0050]). Applicant discloses the specific disruption of deletion of glucocorticoid receptor (GR) (by targeting exon 2 of the NR3C1 gene (Example 13)(Figures 26A-B).
Conclusion
Therefore, the examiner concludes there is insufficient written description support for the instantly claimed genera. Specifically, there is insufficient description of compounds that disrupt expression or activity of TGFBR2 (a)(1) or GR (b)(1) and there is insufficient description of natural killer (NK) cells comprising a disruption of expression or activity of TGFBR2 (a)(2) or GR (b)(2). The specification merely describes massive sub genera of the claimed compounds and disruptions (discussed above). Regarding (a)(1), the specification describes the nucleic acid Trabedersen and 11 gRNA sequences that target TGFB2, these 12 species do not represent the unfathomably large genus of structurally and functionally distinct compounds. Regarding (a)(2), the specific Aon merely describes one disruption which is TGFRB2 deletion in exon 2 made by CRISPR. This one deletion is not representative of such a diverse and vast genus of disruptions. Regarding (b)(1), the specification fails to describe a specific species of the compound, and the general disclosure of types of compounds do not represent the unfathomably large genus of structurally and functionally distinct compounds. Regarding (b)(2), the specification merely describes one disruption which GR receptor deletion by targeting exon 2 of the NR3C1 gene made by CRISPR. This one deletion is not representative of such a diverse and vast genus of disruptions. The instant specification has failed to provide a sufficient number of species to represent the vast and unfathomable number of structurally and functionally diverse species. Further, the specification fails to provide a nexus between the structure of the claimed compounds and NK cells and their claimed function as disrupting expression or activity of TGFBR2. This nexus is not remedied by the state of the art. Thus, in the face of an unpredictable art, one of ordinary skill in the art could not envision the requisite structural elements and the elements that could be modified from the disclosures of the application or art at the time of filing.
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 1-4, 15, 36, 38-39, 42-44 and 58 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 1 recites “a composition comprising two or more of (a), (b), (c), and (d).” However, claim 1 also recites “ the two or more of (a), (b), (c), and (d) may or may not be in the same formulation.” It is unclear how the recited components can be in different formulations (“may not be in the same formulation”) while still being in the same composition. The scope of the claim is therefore indefinite. Similarly, claim 36 recites that “two or more of (a)(1), (a)(2), (b)(1), (b)(2), (c), and (d) are in the same formulation or two or more of(a)(1), (a)(2), (b)(1), (b)(2), (c), and (d)” are in different formulations. Again, It is unclear how the recited components can be in different formulations while being in the same composition as recited in claim 1, upon which claim 36 depends.
The dependent claims are included in the basis of this rejection because they do not clarify the issue.
Claim 25 recites multiple transitional phrases “the composition comprises, consists essentially of, or consists of” which make the metes and bounds of the claim indefinite because it is unclear whether the composition is open or closed to additional components (see 2111.03 for Transitional Phrases). Further, the presence of multiple transitional phrases directly conflicts with Applicant’s species election of “(a)(1) and/or (a)(2) and (b)(1) and/or (b)(2)” which lists components in the alternative. It is unclear how a composition can consist of all the claimed components where the components are required in the alternative.
Claim 43 recites the negative limitation “not the NK cells of” together with a list of alternatives “(a)(2) and/or (b )(2).” The presence of a negative limitation preceding a list of alternatives makes the scope of the claim indefinite because it is unclear whether the negative limitation applies to both alternatives, or just one of the alternatives.
Claim Rejections - 35 USC § 112(b)
Improper Markush
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 1-4, 15, 36, 38-39, 42-44 and 58 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Regarding claim 1, the Markush grouping of two or more of (a), (b), (c), and (d) is improper because the combinations of two or more of (a), (b), (c), and (d) are structurally different entities that impact numerous structurally and functionally distinct pathways.
By nature of their ultimate dependency on claim 1, claims 2-4, 15, 36, 38-39, 42-44 and 58 are also rejected.
Regarding claim 3, the Markush grouping of nucleic acid, peptide, protein, small molecule, or a combination thereof is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Nucleic acids, peptides, proteins, and small molecules are structurally and functionally distinct, and are not the same art-recognized class.
Regarding claim 4, the Markush grouping of siRNA, shRNA, anti-sense oligonucleotides, or guide RNA for CRISPR is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Although the list comprises members which are each RNA, they are structurally and functionally distinct sets of RNA that have distinct secondary structures and distinct functional mechanisms.
Although siRNA and shRNA are both used in RNAi methods, they are structurally distinct and have distinct mechanisms of actions each other and they are also structurally and functionally distinct from guide RNAs and antisense oligonucleotides.
Anti-sense oligonucleotides are structurally distinct from siRNA and shRNA as well as guide RNA and have a functionally distinct mechanism.
Guide RNAs as structurally distinct from siRNA, shRNA and antisense oligonucleotides, and operate thought a functionally distinct mechanism of action (such as CRISPR).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 15, 36, 38, 43-44 and 58 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring product without significantly more. The claims recite compounds or natural killer cells which are not markedly different from its naturally occurring counterpart. This judicial exception is not integrated into a practical application because the natural product is not linked to a particular technology. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional limitations are well understood, routine and conventional.
Applicant is directed to the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019, which is found at: https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf; and the October 2019 Update: Subject Matter Eligibility, which is found at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf.
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
The elected species of (a)(1) and/or (a)(2) and (b)(1) and/or (b)(2) encompasses multiple distinct embodiments that are analyzed and labeled under the two-pronged test below.
In regard to step 1, the claims are directed to composition, which is a product and is a statutory class of invention. Accordingly, the requirements of step 1 are met.
(a)(1) and (b)(1)
In regard to Step 2A prong one, the claims are directed to the combination of (a)(1) and (b)(1) which is directed to a composition comprising
This combination includes in the elected species is the combination of (a)(1) and (b)(1), which is a composition comprising
(1) one or more compounds that disrupt expression or activity of transforming growth factor (TGF)-beta receptor 2 (TGFBR2)
(1) one or more compounds that disrupt expression or activity of glucocorticoid
receptor (GR);
This specific embodiment is directed to a naturally occurring product.
Regarding component (a)(1) of claim 1, Applicant is directed to the art of Lee et al. (Environ Toxicol . 2018 Feb;33(2):248-255. Epub 2017 Nov 9.; henceforth “Lee”). Lee evidences the naturally occurring isoflavane gladbridin, which is found in licorice root (abstract). Lee evidences Gladbridin suppresses the myofibroblast features in fBMFs via TGF-β/Smad2 signaling pathway (abstract), and therefore gladbridin is a compound that disrupt expression or activity of transforming growth factor (TGF)-beta receptor 2 (TGFBR2).
Regarding component (b)(1) of claim 1, Applicant is directed to the art of Whorwood et al. (Endocrinology. 1993 Jun;132(6):2287-92.; henceforth “Whorwood”). Whorwood evidences naturally occurring glycyrrhizic and glycyrrhetinic (GE) acids in licorice which inhibit the enzyme 11 beta HSD (abstract). Whorwood evidences the enzyme 11 beta HSD is a regulator of ligand access to the glucocorticoid receptor (GR). Therefore, the naturally occurring glycyrrhizic and glycyrrhetinic (GE) acids, which inhibit 11 beta HSD, are compounds that disrupt expression or activity of glucocorticoid receptor (GR).
Regarding claim 3, the naturally occurring gladbridin, glycyrrhizic acid and glycyrrhetinic (GE) acid in licorice evidenced by Lee and Whorwood above are small molecules.
Regarding claim 15, the licorice disclosed and evidenced by Lee and Whorwood comprises (a)(1) and (b)(1).
(a)(2) and (b)(2)
In regard to Step 2A prong one, the claims are directed to the combination of (a)(2) and (b)(2) which is directed to a composition comprising
This combination includes in the elected species is the combination of (a)(2) and (b)(2), which is a composition comprising
(a)(2) natural killer (NK) cells comprising a disruption of expression or activity of TGFBR2 endogenous to the NK cells;
(b)(2) natural killer (NK) cells comprising a disruption of expression or activity of GR
endogenous to the NK cells;
This specific embodiment is directed to a naturally occurring product.
Regarding claim 1 (a)(2) and (b)(2), this encompasses encompass NK cells with all possible types and all possible amounts of disruption of expression or activity of TGFBR2 and GR. Therefore, this embodiment is directed to an ordinary population of natural killer cells in mammalian blood that undergo regular fluctuations of expression or activity in of genes including TGFBR2 and GR. Applicant is directed to the art of Rezvani et al (WO-2018/195339-A1; see IDS filed 24th, June, 2022; henceforth “Rezvani1”) which evidences NK cells can be isolated from subjects or donors, and are therefore naturally occurring (para. [0082]). Applicant is additionally directed to the art of Dalle et al. (Pediatr Res. 2005 May;57(5 Pt 1):649-55. Epub 2005 Feb 17.; henceforth “Dalle”) which also evidences naturally occurring NK cells in cord blood (abstract; Figure 1).
Regarding claim 38, cord blood NK cells are naturally occurring in subject cord blood.
Regarding claim 43, the NK cells recited that are not (a)(2) or (b)(2) include embodiments of other naturally occurring NK cells.
(a)(1) and (a)(2) and (b)(1) and (b)(2)
Regarding claim 1 (a)(1) and (a)(2) and (b)(1) and (b)(2), as stated above, the naturally occurring NK cells disclosed by Rezvani1 and Dalle include (a)(2) and (b)(2) due to normal fluctuation in expression included within the breadth of a “disruption” of expression or activity of TGFBR2 and GR.
Regarding claim 1 (a)(1) and (b)(1), the breadth of this element includes all possible nucleic acids, peptide and proteins that regulate TGFBR2 or GR, and therefore includes naturally occurring transcription factors and all possible protein components of the TGFBR2 or GR pathways that naturally occur in the human cord blood and NK cells evidenced by Dalle and Rezvani1 above.
Regarding claim 38, cord blood NK cells are naturally occurring in subject cord blood.
Regarding claim 43, the NK cells recited that are not (a)(2) or (b)(2) include embodiments of other naturally occurring NK cells in the evidenced Cord blood.
In regard to Step 2A prong two, the judicial exception is not integrated into a practical application.
The following additional elements are recited:
(a)(1) and (b)(1) or (a)(2) and (b)(2)
Claim 1 recites the additional element that (a)(1) and (b)(1) of the composition are “may or may not be in the same formulation.” Similarly, claim 36 recites that (a)(1) and (b)(1) are in the same formulation or different formulations. Merely taking the naturally occurring compounds and placing them in a formulation, without additional structure, does not integrate into a practical application.
(a)(2) and (b)(2)
Claim 2 recites the additional element that the NK cells are expanded NK cells. This is product by process language that does not impart and additional structure on the NK cells because merely multiplying the cells ex vivo (expanding), does not impart a markedly different characteristic because they are the same NK cells which comprise the same genotype and phenotype, and therefore does not integrate into a practical application.
(a)(1) and (b)(1) or (a)(2) and (b)(2)
Claim 44 recites the additional element that the composition is comprised
in a pharmaceutically acceptable carrier. Merely placing the naturally occurring compounds into a pharmaceutically acceptable carrier does not integrate them into a practical Application. Further, Applicant is directed to MPEP 2106.04(d)(2) which states that a recitation that a claimed product is a "pharmaceutical composition" is not an affirmative limitation because it are merely indicates how the claimed invention might be used.
Claim 58 recites the additional limitation of a kit comprising the composition. Merely placing the components in a Kit does not integrate into a practical application.
In regard to Step 2B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
As stated above, the following additional elements are recited:
(a)(1) and (b)(1) or (a)(2) and (b)(2)
Claim 1 recites the additional element that (a)(1) and (b)(1) of the composition are “may or may not be in the same formulation.” Similarly, claim 36 recites that (a)(1) and (b)(1) are in the same formulation or different formulations. Merely taking the naturally occurring compounds and placing them in a formulation, without additional structure, does not amount to significantly more.
(a)(2) and (b)(2)
Claim 2 recites the additional element that the NK cells are expanded NK cells. This is product by process language that does not impart and additional structure on the NK cells because merely multiplying the cells ex vivo (expanding), does not impart a markedly different characteristic because they are the same NK cells which comprise the same genotype and phenotype and does not amount to significantly more.
(a)(1) and (b)(1) or (a)(2) and (b)(2)
Claim 44 recites the additional element that the composition is comprised
in a pharmaceutically acceptable carrier. Merely placing the naturally occurring compounds into a pharmaceutically acceptable carrier and does not amount to significantly more. Further, Applicant is directed to MPEP 2106.04(d)(2) which states that a recitation that a claimed product is a "pharmaceutical composition" is not an affirmative limitation because it are merely indicates how the claimed invention might be used.
Claim 58 recites the additional limitation of a kit comprising the composition. Merely placing the components in a Kit and does not amount to significantly more.
Therefore, the claims are directed to naturally occurring licorice or naturally occurring NK cells that are not integrated into a practical application, do not include elements that amount to significantly more than the naturally occurring licorice and NK cells, and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
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.
Claims 1, 3, 15, 36 and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al. (Environ Toxicol . 2018 Feb;33(2):248-255. Epub 2017 Nov 9.; henceforth “Lee”) as evidenced by Whorwood et al. (Endocrinology. 1993 Jun;132(6):2287-92.; henceforth “Whorwood”).
Regarding claim 1, Lee discloses Licorice (abstract). As stated above (see rejection under 35 USC § 101 above, Lee and Whorwood evidence Licorice comprises (a)(1) and (b)(1), discussed below.
Regarding component (a)(1) of claims 1, 15 and 36, Lee evidences the isoflavane gladbridin, which is found in licorice root (abstract). Lee evidences Gladbridin suppresses the myofibroblast features in fBMFs via TGF-β/Smad2 signaling pathway (abstract), and therefore gladbridin is a compound that disrupt expression or activity of transforming growth factor (TGF)-beta receptor 2 (TGFBR2).
Regarding component (b)(1) of claims 1, 15 and 36, Whorwood evidences glycyrrhizic and glycyrrhetinic (GE) acids in licorice which inhibit the enzyme 11 beta HSD (abstract). Whorwood evidences the enzyme 11 beta HSD is a regulator of ligand access to the glucocorticoid receptor (GR). Therefore, glycyrrhizic and glycyrrhetinic (GE) acids, which inhibit 11 beta HSD, are compounds that disrupt expression or activity of glucocorticoid receptor (GR).
Regarding claims 1 and 15, Gladbridin and glycyrrhizic and glycyrrhetinic (GE) acids are all in licorice and a therefore all in the same formulation.
Regarding claim 3, further to the discussion of claim 1 above, Gladbridin and glycyrrhizic and glycyrrhetinic (GE) acids are small molecules.
Regarding claim 44, further to the discussion of claim 1 above, the Gladbridin and glycyrrhizic and glycyrrhetinic (GE) acids are comprised by licorice which can be consumed by a patient and absorbed, and therefore the licorice is a pharmaceutically acceptable carrier.
Accordingly, Lee as evidenced by Whorwood anticipates instant claims.
Claims 1, 3, 15, 36 and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Whorwood et al. (Endocrinology. 1993 Jun;132(6):2287-92.; henceforth “Whorwood”) as evidenced by Lee et al. (Environ Toxicol . 2018 Feb;33(2):248-255. Epub 2017 Nov 9.; henceforth “Lee”).
Regarding claim 1, Whorwood discloses Licorice (abstract). As stated above (see rejection under 35 USC § 101 above, Lee and Whorwood evidence Licorice comprises (a)(1) and (b)(1), discussed below.
Regarding component (a)(1) of claims 1, 15 and 36, Lee evidences the isoflavane gladbridin, which is found in licorice root (abstract). Lee evidences Gladbridin suppresses the myofibroblast features in fBMFs via TGF-β/Smad2 signaling pathway (abstract), and therefore gladbridin is a compound that disrupt expression or activity of transforming growth factor (TGF)-beta receptor 2 (TGFBR2).
Regarding component (b)(1) of claims 1, 15 and 36, Whorwood evidences glycyrrhizic and glycyrrhetinic (GE) acids in licorice which inhibit the enzyme 11 beta HSD (abstract). Whorwood evidences the enzyme 11 beta HSD is a regulator of ligand access to the glucocorticoid receptor (GR). Therefore, glycyrrhizic and glycyrrhetinic (GE) acids, which inhibit 11 beta HSD, are compounds that disrupt expression or activity of glucocorticoid receptor (GR).
Regarding claims 1 and 15, Gladbridin and glycyrrhizic and glycyrrhetinic (GE) acids are all in licorice and a therefore all in the same formulation.
Regarding claim 3, further to the discussion of claim 1 above, Gladbridin and glycyrrhizic and glycyrrhetinic (GE) acids are small molecules.
Regarding claim 44, further to the discussion of claim 1 above, the Gladbridin and glycyrrhizic and glycyrrhetinic (GE) acids are comprised by licorice which can be consumed by a patient and absorbed, and therefore the licorice is a pharmaceutically acceptable carrier.
Accordingly, Whorwood as evidenced by Lee anticipates instant claims.
Claims 1-4, 15, 36, 38-39, 42-44 and 58 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rezvani et al (WO-2018/195339-A1; see IDS filed 24th, June, 2022; henceforth “Rezvani1”).
Regarding claims 1 and 15, Rezvani1 discloses a composition comprising:
(a)
one or more compounds that disrupt expression or activity of transforming growth factor (TGF)-beta receptor 2 (TGFBR2) (“gRNA targeting of Exon 3 of TGFP-RII using gRNA SEQ ID NOs:3-4” Example 3 para. [00265]; see also Example 4)
natural killer (NK) cells comprising a disruption of expression or activity of TGFBR2 endogenous to the NK cells (the immune cell is engineered to have essentially no
expression of TGFβ receptor and “the TGFβ receptor is further defined as TGFβ-RII” para. [0009]) the immune cell is an NK cell, invariant NK cell, NKT cell para. [0007]);
(b)
(1) one or more compounds that disrupt expression or activity of glucocorticoid
receptor (GR) (“gRNA SEQ ID NOs:1-2.” Example 2; para. [00263]; Figure 3; Examples 2-4); and
(2) natural killer (NK) cells comprising a disruption of expression or activity of GR
endogenous to the NK cells (the immune cell is engineered to have essentially no
expression of glucocorticoid receptor (GR) para. [0009]; Example 2-4)
Regarding the wherein clause of claim 1 and regarding claim 36, because (a)(1), (a)(2), (b)(1) and (b)(2) are in the same composition, they are in the same formulation.
Regarding claim 2, further to the discussion of claim 1 above, Rezvani1 discloses the NK cells are expanded (“the NK cells are isolated and expanded” para. [0096]).
Regarding claim 3, further to the discussion of claim 1 above, Rezvani1 discloses the compound that disrupts expression or activity of TGFBR2 comprises a nucleic acid (one or more guide RNAs comprise SEQ ID NOs: 3-4, such as to silence TGFβ para. [0009]) and the compound that disrupts expression or activity of GR comprises a nucleic acid (one or more guide RNAs comprise SEQ ID NOs: 1-2, such as to silence GR para. [0009]).
Regarding claim 3, Rezvani1 also discloses the one or more compounds that disrupt expression or activity of TGFBR2 and/or GR comprises a protein (Cas9 protein; para. [0009]).
Regarding claim 4, further to the discussion of claims 1 and 3 above, as stated above (see claim 3 rejection above), Rezvani1 discloses the nucleic acid comprises gRNA (one or more guide RNAs comprise SEQ ID NOs: 3-4, such as to silence TGFβ para. [0009]; one or more guide RNAs comprise SEQ ID NOs: 1-2, such as to silence GR para. [0009]).
Regarding claim 38, further to the discussion of claim 1 above, Rezvani1 discloses the NK cells are cord blood NK cells or are derived therefrom (para. [0010, 0020, 0028, 0080-0082, 0096, 00260, 00266]; Figures 1A-1C ; Examples 1, 4; claims 22-24; see in particular “umbilical CB is used to derive NK cells” para. [0096]).
Regarding claim 39, further to the discussion of claim 1 above, Rezvani1 discloses in (a)(2) and/or (b )(2) the NK cells are NK cells engineered to express one or more chimeric antigen receptors and/or one or more synthetic T cell receptors (abstract; para. [0003, 0006, 0012-0014, 0026-0030, 0075, 0079, 0084, 00106-00108, 00110-00111, 00126-00133, 00138, 00164, 00266]; Figures 7A-7D; claims 1-2, 4, 30, 41-42).
Regarding claim 42, further to the discussion of claim 1 above, Rezvani1 discloses in (a)(2) and/or (b )(2) the NK cells are engineered to express one or more heterologous cytokines (“hIL-15 or another cytokine such as hIL-21, hIL-2 or hIL-18” para. [0006] “the immune cell is engineered to express one or more additional cytokines” para. [0008] see also para. [0028, 0030-0031, 0066, 0075, 00119, 00137-00138, 00140, 00186, 00187, 00231]; claims 15-16).
Regarding claim 43, further to the discussion of claim 1 above, Rezvani1 discloses the composition further comprises NK cells that are not the NK cells of (a)(2) and/or (b)(2) for several reasons.
First, regarding claim 43, as discussed above, Rezavani1 discloses all of (a)(1), (a)(2), (b)(1) and (b)(2) in compositions. Because the cells of (a)(2) are not necessarily the cells of (b)(2) and vice-versa, the combination of both (a)(2) and (b)(2) includes “cells that are not “(a)(2) and (b)(2)” respectively which are the other cells.
Further, regarding claim 43, Rezvani1 also discloses the NK cells of (a)(2) and/or (b)(2) are made with CRISPR/Cas systems from cord-blood derived NK cells (see Examples 3-5), because CRISPR is not 100% effective, the cells after editing comprise NK cells with neither mutation where editing failed, which are not (a)(2) and/or (b)(2) NK cells.
Regarding claim 44, further to the discussion of claim 1 above, Rezvani1 discloses composition is comprised in a pharmaceutically acceptable carrier (para. [0072, 00232-00233]).
Regarding claim 58, further to the discussion of claim 1 above, Rezvani1 discloses kits comprising the composition of claim 1 (“IV. Articles of Manufacture or Kits” pg. 78-79; para. [00258]), and Rezvani1 discloses suitable housing containers (para. [00258]).
Accordingly, Rezvani1 anticipates instant claims.
Claim Rejections - 35 USC § 102/103
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.
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.
Claims regarding 1-3, 15, 36, 38 and 43-44 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Dalle et al. (Pediatr Res. 2005 May;57(5 Pt 1):649-55. Epub 2005 Feb 17.; henceforth “Dalle”).
Regarding claims 1 and 15, Dalle discloses NK cells in adult blood (abstract; Figure 1). As stated above (see rejection under 35 U.S.C. 101 above), NK cells in adult blood include NK cells that undergo regular fluctuation in expression and activity of TGFBR2 and GR ((a)(2) and/or (b)(2)) respectively, and also include transcription factors that regulate expression of TGFBR2 and GR as well as proteins at all points in the TGFBR2 pathway that regulate their expression or activity ((a)(1) and/or (b)(1)) and therefore the NK cells in the cord blood disclosed by Dalle anticipates (a)(1), (a)(2), (b)(1), and (b)(2) and combinations thereof of instant claims.
Regarding claims 1, 15, and 36, the NK cells and proteins that regulate TGFBR2 and/or GR of Dalle are present in cord blood and are therefore in the same formulation.
Regarding claim 2, further to the discussion of claim 1 above, although Dalle does not specifically disclose the NK cells are expanded, the limitation of “the NK cells are expanded NK cells” is a product by process limitation which does not impart an additional structure on the NK cells. Therefore, the NK cells of Dalle meet the claimed structural limitations
Additionally, regarding claim 2, Applicant is reminded that product-by process claims are not limited by the manipulation of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (see MPEP 2113)
Regarding claim 3, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), the NK cells in cord blood of Dalle include transcription factors as well as all proteins that regulate expression or activity of TGFBR2 and/or GR pathways in all possible ways, which are proteins included in the NK cells and cord blood of Dalle.
Regarding claim 38, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), Dalle discloses the NK cells are cord blood NK cells (abstract; Figure 1).
Regarding claim 43, further to the discussion of claim 1 above, the cord blood disclosed by Dalle also includes other NK cells.
Regarding claim 44, further to the discussion of claim 1 above, the NK cells of Dalle are present in cord blood, which can be delivered to patients and therefore meets the broadest reasonable interpretation of a “pharmaceutically acceptable carrier.”
Alternatively, regarding claims 1-3, 15, 36, 38 and 43-44 if the composition is not directly anticipated because Dalle does not explicitly disclose changes in expression or activity of TGFBR2 and/or GR in NK cells, or the specific proteins that regulate them, then the composition is still prima facie obvious because it is well known in the art that cells undergo regular fluctuation in expression of receptors including TGFBR2 and GR, and it is well known in the art that cells express transcription factors and proteins that regulate receptors pathways including TGFBR2 and GR. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that at least a portion of the cord blood NK cells of Dalle would experience fluctuations in expression or activity of TGFBR2 and/or GR and would also express proteins that regulate these pathways, thus encompassing embodiments of (a)(1), (a)(2), (b)(1), and (b)(2) and combinations thereof of instant claims.
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