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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 21, 2026 has been entered.
Claim Status
Claims 1, 6-10, 46-47 and 49 are currently pending in this application.
Election/Restrictions
Election was made without traverse of Group I, claims 1, 3, and 5, in the reply filed on Aug. 8, 2025, and claims 6-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Claims 1, 46-47, and 49 have been considered on the merits.
Specification
The disclosure is objected to because of the following informalities:
Although the use of trademarks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The use in the specification (e.g., at [0171]-[0203]) of the terms “mTeSR1,” “Matrigel,” “B27,” “Bioruptor,” “Triton X-100,” “AXIO,” and “SurePrint” are trademarks used in commerce (see e.g., [0171]-[0172], Tables 1-2, [0174], [0177], [0193], [0202]-[02023]). The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Appropriate correction at numerous instances in the specification is required because the proprietary nature of trademarks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: because claims 1, 46, and 49 inconsistently use the terms “induced pluripotent stem cells (iPSCs),” “iPS cells,” and “iPS cell.” Appropriate correction is required.
Claim Interpretation
In the claims, the term “iPS cell medium” is interpreted as any medium suitable for culturing iPS cells comprising B27®, WNT3A and activin A, such as RPMI 1640, mTeSR1®, or StemFit® AK02N base medium comprising the aforementioned (see instant [0022], [0174], [0177]).
As claim 49 limits the iPS cells to being human cells, there is an implied limitation that the induced pluripotent stem cells (iPSCs), endodermal cells, and hepatoblasts are human as well.
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, 46-47, and 49 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 claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
The claims are directed to methods for producing hepatoblasts from iPS cells via a method comprising culturing iPS cells, and endodermal cells derived therefrom, in media comprising specifically recited agents, particularly an effective amount of nicotinamide to produce hepatoblasts from the endodermal cells.
Agent Concentrations
In the instant case, the claims are broad in that each culturing step encompasses any agent concentrations other than for nicotinamide. For example, Wnt3A, activin A, FGF2, HGF or dexamethasone typically don’t provide cellular altering activity at picomolar concentrations. Oncostatin M typically has no effect on cells at concentrations under 1 ng/mL. The working examples only show evidence for wherein the B27 is at 1% (v/v), WNT3A is at 50 ng/mL, activin A is at 100 ng/mL, FGF2 is at 10 ng/mL, HGF is at 20 ng/mL, oncostatin M is at 10 ng/mL, and dexamethasone is at 1-100 µM.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of a method to predictably produce hepatoblasts, or even the requisite intermediate endodermal cells, over the scope the claims regarding the two culturing steps lacking any concentrations for the agents in the media. Adequate written description requires more than a mere statement of an intended result of practicing the invention and reference to the broadly claimed method described only at a high level of generality.
Response to Arguments
Applicant’s remarks filed 7/21/26 regarding the written description rejections (pg. 4) have been fully considered but not found persuasive.
Applicant argues that a person of ordinary skill would understand what concentration ranges are suitable for use in performing the claimed method based on the combination of the instant disclosure and the prior art (e.g., for the agents FGF2, HGF, and dexamethasone). However the only support or evidence provided is (1) a discussion of cytokines (relevant to FGF2 and HGF) in a reference regarding expanding hematopoietic stem cells (Branco) wherein the FGF2 concentration used was 5 ng/mL and (2) a discussion of medium component formulations generally from a post-filing date reference (Lipsitz) regarding preparing therapeutic cells for transplantation therapies without teaching any concentration range or value for any of the agents recited in claim 1 but rather how media formulations may be modified during process development. Neither of these references addresses any medium for differentiating iPS cells into endodermal cells nor a serum-free medium for differentiating endodermal cells into TTR+ hepatoblasts.
A quick review of the art suggests the concentration demonstrated in the working example for dexamethasone (1-100 µM) is much higher than typically used in mammalian cell culture media or specifically a serum-free medium for hepatic lineage differentiation, hepatocyte maturation, or hepatocyte maintenance (nanomolar ranges or 25 nM) (see e.g., Goyak et al., Methods Mol Biol 640: 15-138 (2010) at pg. 4). This suggests the effective concentrations of the agents may vary significantly from typically used ranges and further because there are several agents requiring simultaneous optimization, the unpredictability is increased due to this complexity to ensure generation of the required hepatoblasts, e.g., for a method lacking any recitation of a minimum amount of dexamethasone required. However, applicant is invited to furnish evidence to the contrary.
35 USC § 112(a), Scope of Enablement
Claims 1, 46-47, and 49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while enabling the methods of the claims wherein the culturing of the endodermal cells is in a medium comprising at least 0.1 nM FGF2, HGF, and dexamethasone; the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to produce hepatoblasts wherein the FGF2, HGF, and dexamethasone concentrations are unlimited.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "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 USPQ2d 104). Clearly, 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 weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
As noted in the written description rejection, the claims are broad in encompassing an effective amount of nicotinamide and any serum free medium comprising any amount of FGF2, HGF, oncostatin M, and dexamethasone.
The prior art does not directly disclose any such method of making hepatoblasts from iPS cells, meaning the burden lies with applicant’s disclosure.
The working examples only show evidence for where the total culturing is for at least 11 days and wherein the B27® is at 1% (v/v), WNT3A is at 50 ng/mL, activin A is at 100 ng/mL, FGF2 is at 10 ng/mL, HGF is at 20 ng/mL, oncostatin M is at 10 ng/mL, and dexamethasone is at 1-100 µM. The instant specification provides no working example of a method of producing a TTR-expressing hepatoblast for culturing durations less than a few days or wherein the concentration of Wnt3A, activin A, FGF2, HGF or dexamethasone is below 0.1 nM, or wherein Oncostatin M is at concentrations under 1 ng/mL.
Thus, there is no evidence in the instant application or the prior art that the claimed methods could predictably produce hepatoblasts over the full scope of culture conditions.
As the prior art does not directly disclose any such method, it must be emphasized that the skilled artisan of the earliest effective filing date must rely on the written description for guidance, either express or implied, regarding appropriate culture conditions to successfully perform the method. Undue experimentation would be required to fill these gaps in the guidance and unpredictability known in the art.
The prior art does not directly disclose any such method of making hepatoblasts from iPS cells. Instead as noted above, Goyak teaches using nanomolar ranges (e.g., 25 nM) of dexamethasone for hepatocytes and differentiating hepatocytes (pg. 4). This suggests the effective concentrations of the agents may vary significantly from typically used ranges and further because there are several agents requiring simultaneous optimization, the unpredictability is increased due to this complexity to ensure generation of the required hepatoblasts, e.g., for a method lacking any recitation of a minimum amount of dexamethasone required. However, applicant is invited to furnish evidence to the contrary.
Given the extreme breath of the claims, lack of working examples over different culturing durations and agent concentration ranges, the limited guidance provided in the specification, the lack of guidance in the prior art for such broad scope; undue and/or unreasonable experimentation would have been required for one skilled in the art to produce the hepatoblasts as claimed over the full scope of the claimed methods.
Response to Remarks
Applicant’s remarks filed 7/21/26 regarding the previous enablement rejections (pg. 4-5) asserting mootness were considered but do not provide any rationale or evidence.
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, 46-47, and 49 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 1, 46, and 49 each recites the term “iPS” regarding a type of cell or cell medium. If “iPS” is an abbreviation or reference to another term (e.g., an induced pluripotent stem cell), then the full term needs to be spelled out at least once in the claim set so that a person of ordinary skill in the art would understand the limitation of “iPS.” Claim 47 is included in this rejection due to dependence from indefinite claim 1.
Claim 1 recites “the hepatoblasts expressing genes,” which lacks sufficient antecedent basis in the claim. Alternatively, this may be a grammatical typographical error regarding hepatoblasts “express” genes instead of “expressing.” Claims 46-47 and 49 are included in this rejection due to dependence from indefinite claim 1.
Claims 1 and 47 each recites the trademark/trade name B27. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a medium supplement/components and, accordingly, the identification/description is indefinite. Claims 46 and 49 are included in this rejection due to dependence from indefinite claim 1.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 46-47, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Lee (US 9808490 B2) in view of Wang (Wang et al., Stem Cells Dev 24: 2536-46 (2015)) and Sato (Sato et al., Liver 19: 481-8 (1999)).
The claims are interpreted as set forth in a previous section.
Lee teaches a method for producing hepatic progenitor cells (e.g., EpCAM-expressing hepatic stem cells (hepatoblasts)), hepatoblasts (e.g., TTR+, AFP+, HNF4A+ and/or CK19+ cell), and more mature hepatocytes by differentiating endodermal cells (DE cells differentiated from trophoblast stem cells (TS cells)) for 4-6 days in a medium comprising 10 mM nicotinamide, FGF2 (bFGF at, e.g., 10 ng/mL), HGF (e.g., at 5 ng/mL), oncostatin M (OSM) of the IL-6 group (e.g., at 10 ng/mL), and the steroid dexamethasone at, e.g., 0.1 µM (col. 21, lines 19-26; col. 16, lines 29-32; col. 15, lines 13- 17; col. 21, lines 35-45; col. 23, lines 49-65; col. 22, lines 39-47; col. 23, lines 34-41; FIG. 6, 9C, 12-C,E, 14E, Example 2). Nowhere does Lee require the medium comprise serum.
Regarding claim 1, Lee does not teach wherein the endodermal cells are obtained from induced pluripotent stem cells differentiated by culturing in a medium comprising B27, WNT3A, and activin A.
However Wang teaches methods of culturing induced pluripotent stem cells (iPSCs) in a medium comprising B27, Wnt3a (25 ng/mL), and activin A (10-100 ng/mL) to differentiate into endodermal cells (definitive endoderm (DE) cells) (pg. 2539, right col., last para., to pg. 2537, right col., 2nd para.; Abstract; pg. 2543, left col., 1st para., to right col., 1st para.; pg. 2541, right col., last para., to pg. 2542, left col., 1st para.). Also, Sato teaches adding 10 mM nicotinamide to culture medium stimulates hepatocyte proliferation (abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify the method taught by Lee to first comprise a method step of culturing iPS in a medium comprising B27, Wnt3a, and activin A to obtain definitive endoderm cells. One of ordinary skill in the art with the goal of making large amounts of hepatoblasts would be motivated to start with more easily obtainable iPS cells instead of trophoblast stem cell derived DE cells. It also would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify Lee’s culture producing hepatic progenitor cells and mature hepatocytes to include 10 mM nicotinamide. One of ordinary skill in the art with the goal of making large amounts of hepatic lineage cells, such as hepatoblasts, would be motivated by Sato to include the stimulatory agent nicotinamide at an already validated concentration for hepatic lineage cells.
Regarding claim 46, Lee teaches methods lacking Oncostatin M, instead using a different IL-6 group member like IL-6 or lacking HGF (col. 23, last para.; Example 1 produces AFP+ and/or HNF4+ hepatoblasts (FIG. 1E-F, 3C).
Regarding claim 47, Wang teaches wherein WNT3A is excluded and replaced with a GSK-3 inhibitor, such as to improve efficacy or reduce cost (pg. 2539, right col., 1st para.).
Regarding claim 49, Wang teaches wherein the iPSCs are human cells (pg. 2537, left col., para. 2-3).
Thus, the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments filed 7/21/26 regarding the previous 103 rejections (pg. 5-6) were fully considered but not found persuasive. Although Wang teaches replacing WNT3A with a GSK-3 inhibitor due to higher activity and cost, Wang never teaches WNT3A does not work at all, but rather suggests it works less well than the CHIR99021. Thus, Wang does teach and suggest use of WNT3A as was done prior to Wang as Wang has built upon this background. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. See MPEP 2123. "The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed." Id.; see also MPEP 2141.01(VI). Here, Wang may provide discouragement in the form of cost and/or less efficiency but this is not a lack of activity or incompatibility.
Lee teaches making hepatoblasts via definitive endoderm cells (DE) in medium comprising 10 mM nicotinamide, thus this is an effective amount as required by claim 1. Furthermore, Sato teaches specifically including 10 mM nicotinamide for hepatic cells generally, such as differentiating hepatic lineages and maturing hepatocytes; not as a necessity but as an enhancing agent for maturation and expansion.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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