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, 5-10, 44, and 46-49 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was made without traverse of Group I, claims 1, 3, and 5, in the reply filed on Aug. 8, 2025, and claims 6-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim.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, 5, 44, and 46-49 have been considered on the merits.
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 comprising the aforementioned (see instant [0022], [0174], [0177]).
As claim 5 limits the endodermal cells to being derived from human, there is an implied limitation that the iPS cells and hepatoblasts are derived from human. Furthermore, claim 5 is interpreted as requiring an implied method step before the iPS cells culturing step of providing/obtaining iPS cells derived from human, i.e. human iPS cells. Thus, claim 49 is substantially duplicative with claim 5.
Warning: duplicative claims
Applicant is advised that should claim 5 be found allowable, claim 49 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof as explained above. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Previous Rejections
Status of the rejections: the previous claim rejections under 35 USC 112(b) and 103 are withdrawn in view of applicant’s amendments.
Claim Rejections - 35 USC § 112(a) - Written Description (new)
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, 5, 44, and 46-49 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.
In view of dependent claims 44 and 48, the claims are broad in that term “hepatoblast” encompasses hepatoblasts that do not express TTR, AFP, CK19, HNF4A, and/or KI67.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide a single working example of a hepatoblast not expressing TTR, AFP, and/or HNF4A, or any method of making the aforementioned, and thus no exemplary species is disclosed.
While the prior art teaches all hepatoblasts express some level of TTR, AFP, and HNF4A (Su et al., BMC Genomics 18: 946 (2017) at Fig. 4e; pg. 2, left col., last para., to right col., 1st para.; US9808490B2 at FIG. 6, 9C, Table 3), the prior art does not teach the full scope of the term hepatoblast as used in claim 1 absent evidence to the contrary.
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 the full scope of the claimed methods encompassed by the broad term “hepatoblast” encompassing cells that do not express TTR, AFP, and HNF4A. The dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim for all parameters.
Culturing duration and minimum agent concentration
In the instant case, the claims are broad in that each culturing step encompasses any duration and agent concentrations. 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.
While the specification describes culturing steps lasting preferably for at least 4-15 days, the working example only shows evidence after 11 days. The application lacks sufficient disclosure as to produce the recited result of the culturing iPS cell step if the toral duration is less than 7 days (Example 1). Furthermore, the application lacks sufficient disclosure as to produce the recited result if the culturing endodermal cells step lasts less than 4 days or the total of all culturing is less than 11 days (Example 1).
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 unlimited to minimum durations and lacking any minimum 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.
35 USC § 112(a), Scope of Enablement (new)
Claims 1, 5, 44, and 46-49 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 whereby the hepatoblasts express TTR, AFP, and HNF4A, wherein the culturing iPS cells is for at least 4-5 days in a medium comprising at least 0.1 nM WNT3A and activin A, and wherein the culturing endodermal cells is for at least 4 days in a medium comprising at least 0.1 nM FGF2, HGF, and dexamethasone, and at least 1 ng/mL Oncostatin M; 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 that do not express any combination of TTR, AFP, and HNF4A or wherein the culturing durations and agent 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 that the term “hepatoblast” encompass hepatoblasts lacking expression of TTR, AFP, and/or HNF4A. As the prior art does not teach this full scope of “hepatoblast” encompassed by the claims regardless of the their method of production. Thus, these aspects of scope must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue or unreasonable burden being on such artisan.
Also as noted in the written description rejection, the claims encompass any duration of culturing for the two culturing steps, and the claims encompass any amount of WNT3A, Activin A, FGF2, HGF, oncostatin M, and dexamethasone.
The amount of direction and guidance as well as any working examples provided:
The instant specification provides no working example of a hepatoblast, or method of producing a hepatobalst, confirmed to lack expression of TTR, AFP, and HNF4A. Thus, there is no evidence in the instant application or the prior art that the scope of hepatoblasts encompassed by the claims could predictably be produced by any method. Undue experimentation would be required to fill these gaps and unpredictability. Undue experimentation is also required to fill these gaps in the prior art over the breadth of the claims. Given the extreme breath of the claims, lack of any working example, 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 recited hepatoblast genus over their full scope via the methods of any of claims 1, 5, 44, and 46-49.
The working examples only show evidence for 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 hepatobalst 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. Undue experimentation would be required to fill these gaps in the guidance and unpredictability known in the art. 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 hepatoblast and/or endodermal cells over the full scope of the claimed methods.
Claim Rejections - 35 USC § 112(b) (new)
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, 5, 44, and 46-49 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.
The claims are interpreted as set forth in a previous section.
Claims 1, 44, and 48 each recites the term “hepatoblasts”, which is described by the instant specification as including EPCAM-expressing hepatocyte-like cells (also possibly expressing TBX3, TTR, AFP, CK19, DLK, HNF4A, and/or KI67) but that do not necessarily express hepatocyte markers such as A1AT, ALB, G6PC, ASGR1, TAT, TDO2, CYP2C9, CYP2C19, CYP3A4, and CYP7A1 (pg. 27, [0034]; pg. 10, [Figure 1-1](B); pg. 59, [0152], Fig. 1-1A-C and 1-2E); however the prior art and data of FIG. 1-1 teaches hepatoblasts (days 10-21) and maturing hepatocytes (day22+) cannot always be distinguished by the mere presence or absence of ALB, TTR, A1AT, CK19A, or KI67 markers (either via assays of mRNA or protein), with relative expression levels of markers like EpCAM, HNF4A, AFP and/or CD133 serves as better distinctions (Chaudhari et al., Exp Biol Med 241:1653-62 (2016) at Fig. 1). If the applicant acts as her own lexicographer to redefine a term of a claim contrary to its ordinary meaning, the written description must clearly define the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). In the instant case, there is no such clear redefinition, and, thus, the term “hepatoblast” is indefinite, such as how it differs from the term hepatocyte. Claims 5, 46-47, and 49 are included in this rejection for depending from indefinite claim 1. Further, claim 48 is incoherent in view of the prior art discussed above in that more than at least one of the markers recited is inherently present in any cell categorized as a hepatoblast.
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 (iPSC)), 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.” Claims 5, 44, and 47-48 are included in this rejection due to their dependence from indefinite claim 1.
Claims 1 and 46 recite the term “iPS cell medium”, which is not definitively defined in the claims, instant specification or the prior art. A person of ordinary skill in the art reading the claim would not understand the metes and bounds of a “iPS cell” medium. If “iPS” or “iPS cell” is an abbreviation or reference to another term, 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 scope of the limitation. Claims 5, 44, and 47-49 are included in this rejection due to their dependence from claim 1.
Claim 48 recites the phrase “further express” which is incoherent and unclear as nowhere in claim 48 or claim 1 was the expressing of anything else provided to permit the proper use of the term “further.”
Claim 49 recites the limitation that “the iPS cells are human iPS cells,” which is either redundant with claim 5 or conflicts with the interpretation of claim 5 in this office action. If applicant presents a sufficient showing that claim 5 and claim 49 are not redundant, then claims 1, 5, 44, and 46-48 will likely be rejected pursuant to 112(a) for the specification failing to contain an adequate written description across the full scope of the claimed invention and failing in full, clear, concise and exact terms to enable any person skilled in the art to make/use the claimed invention. Applicant may cancel claim 49, amend either claim 5 or 49 to remove indefiniteness and duplicity, rewrite claim 49 in independent form, or present a sufficient showing that claim 49 complies with the statutory requirements in view of claim 5.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 47 and 47 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 46 broadens the scope of claim 1 to wherein the serum-free medium comprises less than all of FGF2, HGF, oncostatin M, and dexamethasone.
Claim 47 broadens the scope of claim 1 to wherein the iPS cell medium comprises less than all of B27, WNT3A and activin A.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103 (new)
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, 3, 5, 43-44, and 46-49 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)).
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 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).
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 these cells 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.).
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.
Regarding claim 5, Lee teaches wherein the DE cells are human cells (col. 19, lines 10-13).
Regarding claim 44, Lee teaches wherein the hepatoblasts comprise TRR-expressing hepatoblasts (col. 29, lines 7- 26; col. 2, lines 21-27 and 61-67).
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 (pg. 2539, right col., 1st para.).
Regarding claim 48, Lee teaches wherein the hepatoblasts comprise AFP expressing hepatoblasts (FIG. 1E-F, 3C, 6, 9C, 12C,E).
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.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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