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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on March 12, 2026.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 12, 2026 has been entered.
Claims 1-9, 11-13, 18-20 and 24-37 are currently pending. Claims 1, 6, 18, 20, 24, 32 and 33 are independent. No new claims are added or canceled and claim 1 is amended.
Therefore, claims 1-9, 11-13, 18-20, and 24-37 are examined on the merits.
The examiner acknowledges previously receiving an executed Declaration under 37 C.F.R. § 1.132 executed by Dr. Takanori Takebe on September 10, 2025 (“Takebe Declaration ”), and filed on 09/10/2025.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112(a)
The rejection of claims 1-5, 20, 25-29 and 32-37 under 35 U.S.C. 112, first paragraph regarding the scope of enablement is withdrawn.
Applicant’s arguments and amendments filed 03/12/2026 have been considered and are persuasive. Particularly the concentration of RA being newly defined in the claims within the scope of the invention.
Double Patenting
The rejection of claim 1-9, 11-13, 18-20, and 24-37 on the ground of nonstatutory double patenting as being unpatentable over claim 1-17 of US Patent No. 12428622 is withdrawn.
Applicant’s arguments and amendments filed 03/12/2026 have been considered and are persuasive. Particularly that the invention is distinct from the present invention due to the method of producing HSCs from the liver organoid where foregut cells are cultured in the absence of retinoic acid..
Claim Rejections - 35 USC § 103
The rejection of claim 6, 11 and 13 under 35 U.S.C. 103 as being unpatentable over Sato (US20120196312) in view of Gissen et al. (2015. J Hepatol 63(4): 1023–103) has been withdrawn .
Applicant’s arguments and amendments filed 03/12/2026 have been considered and are persuasive. Particularly that the references do not provide for either individually or in combination a reasonable expectation of success in producing MSCs within a liver organoid.
The rejection of claim 8 under 35 U.S.C. 103 as being unpatentable over Sato (supra) in view of Gissen et al. (supra) as applied to claim 6, above, and in further view of Ramachandran et al. (2015. PLOs One 10(10): 1-12; IDS Reference filed on 09/10/2019) has been withdrawn.
Applicant’s arguments and amendments filed 03/12/2026 have been considered and are persuasive. Particularly that the references do not provide for either individually or in combination a reasonable expectation of success in producing MSCs within a liver organoid.
The rejection of claims 9, 30, and 31 under 35 U.S.C. 103 as being unpatentable over Sato (supra) in view of Gissen et al. (supra) as applied to claim 6 above, and in further view of Ng2 (US20180258400; IDS Reference) has been withdrawn.
Applicant’s arguments and amendments filed 03/12/2026 have been considered and are persuasive. Particularly that the references do not provide for either individually or in combination a reasonable expectation of success in producing MSCs within a liver organoid.
The rejection of claim 12 under 35 U.S.C. 103 as being unpatentable over Sato (supra) in view of Gissen et al. (supra) as applied to claim 6 above, and in further view of Markova et al. (2013. Clin Pharmacol Ther. 94(6):678-86; IDS Reference filed 09/10/2019) has been withdrawn.
Applicant’s arguments and amendments filed 03/12/2026 have been considered and are persuasive. Particularly that the references do not provide for either individually or in combination a reasonable expectation of success in producing MSCs within a liver organoid.
The rejection of claim 18, 19 and 24 under 35 U.S.C. 103 as being unpatentable over Sato (supra) in view of Gissen et al. (supra) as applied to claim 6 above, and in further view of Ortega (US2013/0189327; IDS Reference 022 filed on 02/26/2021) and Ortega2 (US2017/0191030, US filing date: May 2015; IDS filed 02/26/2020) has been withdrawn.
Applicant’s arguments and amendments filed 03/12/2026 have been considered and are persuasive. Particularly that the references do not provide for either individually or in combination a reasonable expectation of success in producing MSCs within a liver organoid.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Double Patenting
Claim 1-9, 11-13, 18-20, and 24-37 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-5, 24-27, and 29-41, of (formerly copending) Application No. 16/611,998 which has since been allowed on 8/11/2026 (issue fee payment 08/24/2026). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of 16/611,998 recite a genus for which the claims in the current application are the species.
Application ‘998 recites a liver organoid made by the same process with the same method steps expressing the same markers which would inherently be the liver organoid of the present application. The singular difference in claim language between Claim 1 and Claim 1 of ‘998 is the presence of a wnt activator, however in Claim 31 of ‘998, GSK3 inhibitors are included in the genus of Wnt signaling pathway activators.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
In response to Applicant’s arguments against the Double Patenting rejection of claims 1-9, 11-13, 18-20, and 24-37
Applicant’s arguments have been considered, however they are not persuasive. Applicant argues that the invention is distinct. However, only arguments regarding the previously set forth rejection of Patent ‘622 are present.
Therefore, the rejection of newly patented Application ‘998 is maintained.
New objections/ Rejections in response to Applicants’ arguments or amendments
Claim objections
Claim 1 is objected to because of the following informalities: abbreviations such as FGF and GSK3 should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claims 11 and 34 improperly states their intended Markush groups; the proper format requires the use of “one or more genes selected from the group consisting of” and “said liver damage is selected from the group consisting of”. Appropriate correction is required.
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 6-9, 11-13, 20, 24 and 32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
The most recent update to the Office' s patent eligibility requirements are the 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG) published on January 7 and October 19, 2019 (84 Fed. Reg. 50), which provides the following analysis to determine patent eligibility, derived from the decisions rendered in Mayo Collaborative Svcs. v. Prometheus Labs., 566 U.S. __, 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012) (hereinafter “Mayo”), and in Alice Corp. Pty. Ltd. v CLS Bank Int' l, 573 U.S. __, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014) and subsequent court cases:
Step 1 is to determine whether the claim is directed to a process, machine, manufacture, or composition of matter. If the claim is directed to a statutory category, proceed to Step 2.
Step 2 is the two-part analysis from Alice Corp. (also called the Mayo test).
Step 2A has been divided into 2 prongs.
Step 2A, prong 1 requires determining whether the claim is directed to the judicial exceptions of an abstract idea, a product of nature, or a law of nature or natural phenomenon other than a product of nature. To determine if the claim recites a nature-based product limitation, the markedly different characteristics analysis is used to evaluate whether the claim is directed to a “product of nature” that falls under the law of nature and natural phenomenon exceptions. In this analysis, markedly different characteristics can be expressed in terms of the product' s structure, function, and/or other properties. If YES, the claim is directed to a judicial exception, proceed to step 2A, prong 2.
Step 2A, prong 2 requires evaluating whether a judicial exception is integrated into a practical application (e.g. improving technology, effecting a particular treatment or prophylaxis, implementing with a particular machine, etc.) identified by the Supreme Court and the Federal Circuit, to ensure that the claim as a whole “integrates [the] judicial exception into a practical application [that] will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the judicial exception.” If NO, the claim does not integrate the judicial exception into a practical application, then proceed to step 2B.
Step 2B requires analyzing whether the claim as a whole amounts to significantly more than the exception by determining whether any element, or combination of elements, in the claim is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception. To be patent-eligible, a claim that is directed to a judicial exception must include additional features to ensure that the claim describes a process or product that applies the exception in a meaningful way, such that it is more than a drafting effort designed to monopolize the exception. The Supreme Court has identified the following non-limiting considerations for determining whether a claim with additional elements amounts to significantly more than the judicial exception itself:
• Improvements to another technology or technical field;
• Improvements to the functioning of the computer itself;
• Applying the judicial exception with, or by use of, a particular machine;
• Effecting a transformation or reduction of a particular article to a different state or thing;
• Adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application; or
• Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
The claims recite “A liver organoid derived from a stem cell, wherein said liver organoid comprises a luminal structure comprising internalized microvilli and mesenchymal stem cells; and wherein said luminal structure is surrounded by polarized cells” and “A liver organoid made by the method of claim 1.” Claims 20 and 24 are directed to a method of testing a candidate compound using a liver organoid.
Regarding step 1, the claims are directed towards compositions of matter.
Regarding step 2A prong 1, the liver organoid claimed in the present application is a product of nature and is not markedly different than its naturally occurring counterpart, the liver, which it models.
Regarding step 2A prong 2, this judicial exception is not integrated into a practical application because the liver organoids in subsequent claims simply say that they are used to test compounds with the organoid and transplanted into patients for treating liver damage and according to MPEP2106.95(f) the additional element or combination of elements must do "‘more than simply stat[e] the [judicial exception] while adding the words ‘apply it’".
Regarding step 2B, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the only elements recited are the luminal structure, microvilli, and MSCs surrounded by polarized cells.
Gissen((2015. J Hepatol 63(4): 1023–103) teaches the structural and functional polarity of hepatocytes within the liver which are uniquely organized with a basal membrane facing liver sinusoidal endothelial cells (Abstract). Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and the hepatocytes give rise to the bile canaliculus which has microvilli (p. 1023). These microvilli dramatically increase the surface area of the bile canaliculus for absorption and a lack of microvilli can result in liver disease and malabsorption (p. 1023, 1028, 1030). Luminal structures are naturally formed by hepatocytes (Fig 1).
Wang (Stem Cell Research & Therapy (2016) 7:71) teaches MSCs are found within the fetal and adult liver (p. 1-2, bridging section).
Therefore, the liver organoids of the present application are rejected as being directed towards a judicial exception without significantly more.
Claim Rejections - 35 USC § 112
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 18-19 and 33-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification does not reasonably provide enablement for a method of treating an individual having liver damage comprising implanting the liver organoid.
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 the claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
The nature of the invention;
The breadth of the claims;
The state of the prior art;
The level of skill in the art;
The level of predictability in the art;
The amount of direction provided by the inventor;
The presence or absence of working examples;
The quantity of experimentation necessarily needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
Claims 18 and 33 recite “a method of treating an individual having liver damage comprising implanting the liver organoid.” This encompasses a wide range of administration methods, locations of implantation, and effectiveness in treating various symptoms associated with liver damage.
However, the present application lacks enablement for treating liver damage with organoids. There is a lack of working examples directed towards implantation and treatment of disease or disorders, and the only mention of implantation/transplantation in a list of possible uses (See para. 0042-0043, 0057).
Moreover, the state of the art at the time of filing, Huppert (Curr Opin Organ Transplant. 2016 December ; 21(6): 581–587) teaches that “Further advancement of the liver organoid system in combination with iPSC differentiation will enlighten the critical cellular and molecular mechanisms required for both liver organogenesis and potential liver replacement therapies” (p. 7, last full paragraph). “Liver tissue engineering options, such as decellularized scaffolds and self-organizing organoids, composed of multiple cells types hold the potential for developing extrahepatic site transplantation procedures” (p. 13, Key Findings).
Therefore, the state of the art has not demonstrated the treatment of liver damage with implanted liver organoids which would inform one of ordinary skill in the art outside of the instant specification. The lack of guidance from both the disclosure and the state of the art cause a level of undue experimentation for one of skill in the art to treat liver damage with an organoid.
Therefore, the claims lack enablement.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 3 is 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 applicant regards as the invention.
Claim 3 recites “said foregut spheroids”. There is not proper antecedent bases for “said foregut spheroids”. Claim 1 recites “posterior foregut spheroids”. Appropriate correction is requested.
Allowable Subject Matter
Claims 1-5, 25-29 and 35-37 directed towards the method of producing the liver organoid with the unexpected concentration of RA would be allowable if a terminal disclaimer is filed. All other claims would need to be canceled.
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
