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 .
Election/Restrictions
Applicant's election without traverse of invention group I, drawn to a method for producing a kidney organoid, in the reply filed on 3/9/2026 is acknowledged.
Applicants request to rejoin Group V, claim 11, drawn to a method for promoting the maturation of proximal tubule was accepted.
Claims 6-10, 12-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species/invention.
Claim status
Claims 1-18 are pending.
Claims 1-6 , 11 are under examination.
Claim interpretation
Specification refers to ‘early kidney organoid’ as an organoid comprising one or more renal vesicles that are LHX1 positive, in description of embodiments (page 10). However, the specification doesn’t define renal vesicles or recite if the said LHX1 positive vesicles are in or outside the cells. Therefore, given the reference to organoid as a three-dimensional cell aggregate formed in vitro and resembling biological tissue (page 9), the broadest reasonable interpretation (BRI) of the early kidney organoid was arrived as a ‘three-dimensional cell aggregate formed in vitro, resembling a biological tissue, positive for LHX1 either inside or outside the aggregate’.
The mature proximal tubules are interpreted to have any proximal tubule marker. Specification recites a list of markers in the mature proximal tubules in embodiments (page 10) which is not a definition. Therefore, proximal tubules markers are broadly interpreted to be at least one known proximal tubule marker..
Claim objections
Acronyms RXR and PPAR are not defined in claim 1,
Acronym GSK3β is not defined in claim 3,
please define the acronyms at the first recitation.
Specification
The disclosure is objected to because of the following reasons:
Specification page 43, paragraph 0151 recites lists of PPARA-related genes, PPARG-related genes, and RXR-related genes. The recited lists under each group are not genes but appear to be drugs/agonists.
Appropriate correction is required.
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.
Claim 3, recites an induction medium A and an induction medium B. The claim is dependent on claim 2 which recites an induction medium A and an induction medium B. It is not clear if claim 3 refers to the media in claim 2 or a different A and B media. The claim appears to lack antecedent basis. Therefore, the claim is indefinite.
Claim Rejections - 35 USC § 112(a)
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 1-6 and 11 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.
Sope of the invention
The instant claims are drawn to a method for producing a kidney organoid, comprising culturing the said kidney organoid in a medium containing RXR agonist and a PPAR agonist. The specification recites examples of only one combination of XRX and PPAR agonists, i.e 9-cis retinoic acid and CP775146 used in the medium for producing a kidney organoid.
Though the claimed genera XRX agonist and PPAR agonist, are broadly encompassing numerous molecules, the specification only support producing a kidney organoid in the presence of 9-cis retinoic acid and CP775146 i.e., a RXR agonist and a PPAR agonist respectively.
Structure/function relationship
Retinoic X receptors (RXR) are Type 2, heterodimeric nuclear receptors which are proteins that bind to DNA, regulating cellular functions such as growth, differentiation and metabolism (Almeida et al., 2019, introduction, pages 1and 2). The instant specification recites a list of RXR agonists that may be used in the claimed method of producing kidney organoid, including 9-cis retinoic acid, TTNPB and bexarotene. The said list of molecules have distinct structures and form distinct heterodimers of RXRs when bound to their target nuclear receptors and execute different effects as discussed below.
Mechanistic investigations of RXR agonists 9-cis-retinoic acid and other retinoid family molecules such as ATRA, retinol and retinal have shown that their actions are attributed to binding to both retinoic acid receptors (RARs) and RXRS. Upon ligand binding RAR/RXR dimer interacts with retinoic acid response elements triggering downstream events such as cell differentiation, arrest and apoptosis. The biological role of RARS of the said heterodimer is to regulate cellular differentiation and proliferation, while RXR generally regulate cellular apoptosis (Almeida et al., 2019, RXR agonists 3.1, pages 5-6). RXR agonist bexarotene is known to activate RXR/Nurr1 heterodimers. Nurr1 has an essential function in development and maintenance of dopamine neurons (Almeida et al., 2019, RXR agonists 3.3, page 8). Also, TTNPB is a RAR selective ligand which has shown to promote cell death when applied in combination with RXR agonists (Almeida et al., 2019, RXR agonists 3.4, page 10).
Peroxisome proliferator activated receptors (PPARs) are ligand -activated nuclear receptors which are also transcription factors (Kota et al., 2005, abstract, page 85). Upon activation by natural or synthetic ligands, PPAR dimerize with RXR to carry out the desired transcription (Kota et al., 2005, fig.2, page 86). Kota teaches three PPAR isoforms encoded by separate genes. The instant specification recites lists of PPARA, PPARG, PPARD, PPARA/G,PPARA/D and PPARG/D agonists that may be used in the claimed method of producing kidney organoid.
Each PPAR isoform varies in ligand specificity, tissue distribution and lead to specific biological implications, upon ligand-receptor binding. For example, activation of PPAR-α by its specific agonists have implications on atherosclerosis and inflammation, while activation of PPAR-β by specific agonists have implications in infertility, hyperglycemia and hyperlipidemia as well as atherosclerosis (Kota et al., 2005, table 2, page 88, conclusion and future research, page 91). In-depth investigations are needed to fully understand the PPAR mediated biological mechanisms (Kota et al., 2005, conclusion and future research, page 91).
As discussed above, various RXR agonists and PPAR agonists that specifically bind various isoforms have distinct structures and functions.
Conclusion
As evidenced by the prior art (Almeida et al., 2019, Kota et al., 2005), instantly claimed genera; RXR agonist and PPAR agonist have heterogenous effects. Specification lacks proof to support the claims as recited that all the molecules encompassing RXR and PPAR agonists can be employed in the claimed method for producing a kidney organoid. Therefore, the examiner concludes there’s insufficient written description for the instantly claimed genera. Specification fails to reasonably convey to one skilled in the relevant art that the inventors, at the time of effective filling date of the application, had possession of the entire scope of the claimed invention.
Claim Rejections - 35 USC § 112 (a)
Claims 1-6 and 11 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 producing a kidney organoid, comprising; culturing an kidney organoid with medium containing 9-cis retinoic acid and CP775146, wherein the kidney organoid includes matured proximal tubule cells does not reasonably provide enablement for producing a kidney organoid, comprising; culturing an kidney organoid with medium containing any combination of RXR and PAR agonists, wherein the kidney organoid includes matured proximal tubule cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to utilize 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:
The claims are drawn to a method for producing a kidney organoid.
(2) Breadth of the claims:
The instant claims are drawn to a method for producing a kidney organoid, comprising culturing the said kidney organoid in a medium containing any RXR agonist and any PPAR agonist.
(3) The state of the prior art:
In the last decade, the use of kidney organoids have become a useful tool for studying various kidney diseases as well as drug development and screening (Chen et al., 2021, introduction). Growing kidney organoid in culture media in the presence any RXR agonist and any PPAR agonist is not well known/validated in the art.
Retinoic X receptors (RXR) and peroxisome proliferator activated receptors (PPARs) are ligand-activated, heterodimeric, nuclear receptors which are also transcription factors (Almeida et al., 2019, introduction, pages 1 and 2, Kota et al., 2005, abstract, page 85).
Various RXR agonists have distinct structures and form distinct heterodimers of RXRs when bound to their target nuclear receptors and execute different downstream biological effects (Almeida et al., 2019, introduction, pages 1 and 2) .
For example, RXR agonists 9-cis-retinoic acid and other retinoid family molecules such as ATRA, retinol and retinal activates both retinoic acid receptors (RARs) and RXRS. Upon ligand binding RAR/RXR heterodimer interacts with retinoic acid response elements present on DNA, triggering downstream events such as cell differentiation, arrest and apoptosis (Almeida et al., 2019, RXR agonists 3.1, pages 5-6). RXR agonist bexarotene is known to activate RXR/Nurr1 heterodimers. Nurr1 has an essential function in development and maintenance of dopamine neurons (Almeida et al., 2019, RXR agonists 3.3, page 8). Also, TTNPB is a RAR selective ligand which has shown to promote cell death when applied in combination with RXR agonists (Almeida et al., 2019, RXR agonists 3.4, page 10).
Kota teaches three PPAR isoforms encoded by separate genes. Upon activation by natural or synthetic ligands, PPARs dimerize with RXR to carry out desired transcription (Kota et al., 2005, fig.2, page 86). Each PPAR isoform varies in ligand specificity, tissue distribution and lead to specific biological implications when activated. For example, activation of PPAR-α by its specific agonists have implications on atherosclerosis and inflammation, while activation of PPAR-β by have implications in infertility, hyperglycemia and hyperlipidemia as well as atherosclerosis (Kota et al., 2005, table 2, page 88, conclusion and future research, page 91). Therefore, as discussed above, various RXR agonists and PPAR agonists have distinct structures and functions.
(4) The predictability or unpredictability of the art:
Current status of prior art regarding methods of generating kidney organoids are unpredictable. Due to the numerous cell types present in kidneys, the various protocols that have been developed over the past decade vary in complexity and the number of cell types present (Chen et al., 2021, introduction). Almeida et al., 2019 point out that optimizing and designing RXR agonists that are selective for only one RXR sub-class has been a challenge, and more work is needed in optimizing the structure and function of the agonists (conclusion, page 17). Kota et al. 2005, point out the need for in-depth investigations to fully understand the PPAR mediated biological mechanisms (conclusion and future research, page 91).
(5) The relative skill of those in the art:
The relative skill of those in the art is high, requiring a graduate degree.
(6) The amount of guidance presented:
Claims and specification when taken together do not provide sufficient guidance to successfully produce kidney organoid in the presence of any RXR and PPAR agonists. Specification recites list of RXR and PPAR agonists that may be used in producing the said kidney organoid. However, the disclosure only provide evidence of using either the combination of XRX and PPAR agonists, 9-cis retinoic acid and CP775146 or the PPAR agonist pirinic acid alone in the making of kidney organoid. Specification lacks evidence of any other RXR and PPAR agonists.
(7) The presence of working examples:
Specification recite working examples 1- 9, and comparative examples 1-2.
Example 1 recites a single cell RNA sequencing analysis of cultured kidney organoids without RXR or PPAR agonists (organoids produced by step A and B shown in the flow chart on fig.1), results indicating the activation of PPARA-related genes, PPARG-related genes and RXR-related genes which led to the indication that mature cells can be induced in a kidney organoid culture by using a PPARA agonist, PPARG agonist, or a RXR agonist or a combination thereof. The results are not shown in a graphical illustration, and the recited ‘PPARA PPARG and RXR genes ’on specification paragraph 0150, don’t appear to be genes (please see objection specification).
Examples 2-5 disclose the production of kidney organoid including the mature proximal tubule cells when the organoids were cultured in an induction medium C containing either one or the combination of RXR and PPARA agonists, 9-cis retinoic acid and CP775146 respectively. Figs 2-5 shows the expression levels of mature proximal tubule markers at different concentrations of the 9-cisretinoic acid and CP775146. The said markers showed highest expression in the presence of both, 9-cis retinoic acid and CP775146
Comparative examples 1 and 2 illustrate the expression level of maturation markers of the proximal tubules when the organoid was cultured in PPARA antagonist GW6471 (fig. 12), and RXR antagonist HX531 (fig. 13). The said antagonists appear to prevent early induction of differentiation into matured proximal tubule cells.
Example 9, disclose the production of kidney organoid in the presence of PPARA agonist, pirinic acid (WY14643), instead of the combination of PPARA agonist (CP775146) and RXR agonist (9-cis retinoic acid ). Fig.14 shows that pirinic acid alone increased the expression of proximal tubule markers. However, given the heterogeneity of the PPAR and RXR agonists as discussed above, it is not an indication that combining pirinic acid with an RXR agonist may promote maturation of proximal tubular cells as recited in the specification (0192).
Therefore, the specification enables an ordinary artisan to culture kidney organoid in the presence of the combination of 9-cis retinoic acid and CP775146 or pirinic acid alone, wherein the kidney organoid includes matured proximal tubule cells.
However, the specification do not provide working examples of any other RXR or PPAR agonists.
(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 use the claimed invention within the broad scope as instantly claimed. For example, one of ordinary skill in the art would have to perform an undue amount of experimentation to determine what combination of the RXR and PPAR agonists would facilitate the production of the claimed kidney organoid.
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 5-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature without significantly more.
The claims 5-6 recite ‘a kidney organoid including proximal tubule cells’ . According to the 2019 Revised Patent Subject Matter Eligibility Guidelines (2019PEG), the claim is first analyzed to determine if it is directed to one of the acceptable statutory categories (i.e. process, machine, manufacture, or composition of matter). Claims 5-6 are drawn to a composition of matter comprising ‘a kidney organoid including proximal tubule cells’. Thus claim 5-6 meet the requirements for step 1 of the analysis.
Second, the claims are assessed to determine if they are directed to a judicial exception under step 2A. Under 2019PEG, “directed to” is determined via a two-prong inquiry: (1) Does the claim recite a law of nature, a product of nature, a natural phenomenon, or an abstract idea; and (2) Does the claim recite additional element(s) that integrate the judicial exception into a practical application. The phrase, “integration of a practical application”, requires the presence of an additional claim element(s) or a combination thereof to apply, rely on or use the judicial exception in a manner that imposes a meaningful limitation on the judicial exception, such that the claim does not monopolize the judicial exception. (See MPEP § 2106.05 for examples of integration of practical application).
Regarding the first prong (1), claims 5-6 are directed to ‘a kidney organoid including proximal tubule cells’. According to the broadest reasonable interpretation of the early kidney organoid ‘three-dimensional cell aggregate, resembling a biological tissue, positive for LHX1 either inside or outside the aggregate’ (see claim interpretation), the structure of a kidney organoid including proximal tubule cells is an exact match for a sample of in vivo kidney. Thus, the first prong of the inquiry demonstrates that claims 5-6 recite a judicial exception, a product of nature.
Regarding the second prong (2), Claims 5-6 recite additional elements that a kidney organoid including proximal tubule recited in each claim is “produced” by the method according to claim 1. The recited method solely describe the means by which the claimed kidney organoid is made. Thus, since the additional element solely describe a means by which the kidney organoid is made, the claims 5-6 do not recite any additional elements or a combination thereof that integrate the judicial exception identified in prong 1 into a practical application. Further, since the claims 5-6 are not meaningfully limited to any particular practical application, the generic nature of the claim appears to monopolize the claimed method. Thus, claims 5-6 meet the requirement of step 2A as being directed to a judicial exception.
Third, if a judicial exception is present in the claim, it is further assessed to determine if the claim recites any additional elements or steps that are sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception. As discussed above, the claims recite the structural element of “produced”. It is noted that “produced” does impart a structural distinction to the claimed kidney organoid in claims 5-6 because in nature kidney organoid or kidney cell aggregates are not produced but rather are found in vivo. However, the claimed produced kidney organoids are structurally indistinguishable from the kidney cell aggregates in vivo, because they are naïve or unaltered having the same structural and functional features of kidney samples in vivo.
Thus, as a whole, claims 5-6 do not impart any structural or functional distinctions to the claimed ‘kidney organoid’ that would distinguish it from a kidney sample found in nature. As such, claims 5-6 do not meet the requirements of step 2B of the 2019PEG because the produced kidney organoid and the method by which the claimed organoid was prepared do not impart a significant distinction to the claimed kidney organoid to distinguish them from kidney samples in vivo.
In conclusion, claims 5-6 meet all the requirements of the 2019PEG and therefore deemed patent ineligible.
Conclusion
No claim is allowed
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/HASHANTHI KOMITIGE ABEYRATNE-PERERA/ Examiner, Art Unit 1632
/MARCIA S NOBLE/ Primary Examiner, Art Unit 1632
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