DETAILED ACTION
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.
Claims 33, 35, and 37-55 were previously pending.
Claims 40-51 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Receipt is acknowledged of the Claim Amendments filed on 23 March, 2026. Claims 33, 38, 39, and 52-55 are amended. Claims 35, 37, and 40-51 are cancelled. Claims 56-59 are newly added.
Therefore, claims 33, 38-39, and 52-59 are pending and are the subject of the present Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2021/007490, filed 26 February, 2021, which claims priority to Japan Application No. JP2020-032139, filed 27 February, 2020. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified untranslated copies of papers required by 37 CFR 1.55 have been filed in this application on 26 August, 2022.
The earliest possible priority for the instant application is 27 February, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 23 March, 2026 and 09 October, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
Receipt is acknowledged of the replacement drawings submitted on 23 March, 2026. Applicant has failed to correct all issues raised in the objection to the drawings issued in the Non-final rejection of 25 November, 2025. Remaining grounds of objection are set forth below.
The drawings remain objected to because some have legends overlapping axis labels. Fig. 20-22 have legends overlapping and occluding axis labels. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Figures 85, 86, 87, 88, 90, 105, 107, 108, 112 and 113 remain objected to under 37 CFR 1.83(a) because they fail to show any details as described in the specification. Specifically, the figures are photographs of cell cultures. However, the details are indiscernible as the image is too dark. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). A proposed drawing correction or corrected drawings are required in reply to the Office action to avoid abandonment of the application. The objection to the drawings will not be held in abeyance.
Specification
The objection to the disclosure because of the following informalities: the tables are illegible with special note to those on pages 69, 90, 123, 125, 128, 129, and 135 is withdrawn in view of Applicant’s amendments to the specification. Applicant has replaced all tables with legible versions.
Examiner’s Comment
Throughout the present Action, where reference is made to the instant specification, the Examiner will refer to the publication of the instant Application for ease of citation (US2023/0257700).
Claim Objections
The objection to claim 38 because of the following informalities: “ion channel”, and “monocarboxylic acid transporter” are missing a definite article (e.g. “a”) is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended the claim to add the appropriate definite articles.
Claim Interpretation
The recitation of “capable of eliciting a human corneal function when infused into an anterior chamber of a human eye” is a property of the product within the method claimed. It is noted that where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). Thus, for the purpose of applying prior art, a disclosure of an identical or substantially identical product is presumed to inherently possess the claimed properties. See MPEP 2112.01. The same is true for the recited properties within claim 38. To the extent a recited property in claim 38 requires the presence of additional structures, those will also be required by a prior art cell for said cell to be interpreted as inherently possessing the recited properties. For example, a prior art cell cultured under the conditions claimed in claim 33 and possessing an ion channel as recited in claim 38(iv) will be presumed to inherently possess the properties of “capable of eliciting a human corneal function when infused into an anterior chamber of a human eye” and “a corneal endothelial (cell) functional property leading to improvement on corneal opacity and hydrous edema, resulting in continuous and long-term retention of corneal endothelial tissue cell density and improvement on visual acuity”.
Withdrawn Rejections in view of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 112
The rejection of claim 39 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 is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claim 39 to narrow the scope of the claim on which it depends.
Claim Rejections - 35 USC § 102
The rejection of claims 33, 35, 37-39, 52, and 54 under 35 U.S.C. 102(a)(1) as being anticipated by Toda, et al. Investigative ophthalmology & visual science 58.4 (2017): 2011-2020., hereinafter “Toda” as evidenced by Mohamed et al. Blood research 55.1 (2020): 35., “hereinafter “Mohamed” is withdrawn in view of Applicant’s amendments to the claims.
Applicant has amended the claims to require less than 1ng/mL EGF. Toda plainly requires 5 ng/mL EGF.
The rejection of claims 33, 35,37-39, and 52-55 under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017/141926, hereinafter “Hamuro”, cited on the IDS submitted 26 August, 2022 is withdrawn in view of Applicant’s amendments and arguments.
Applicant has amended the claims to require less than 1 ng/mL EGF. Applicant argues that Hamuro’s examples all require 5 ng/mL EGF and that the mere fact that claim 21 does not recite EGF cannot be interpreted as Hamuro affirmatively claiming or disclosing the lack of EGF. This argument has been fully considered and has been found persuasive because Hamuro is primarily drawn to the cells themselves and uses of the cells with recitations of the method of obtaining the cells always requiring 5 ng/mL EGF. Accordingly, this rejection is withdrawn.
Maintained Rejections in view of Applicant’s Amendments and Arguments
The rejection of claims 33, 35, 37-39, and 52-55 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn with respect to claims 33, 38, 39, 52-55, rendered moot by applicant’s cancellation of claims 35, and 37, and maintained with respect to claim 38 as necessitated by Applicant’s amendments to the claims.
Amended claim 38 now recites “increased” in steps (ia), (ib), (v) and (vi). The term “increased” is a relative term which renders the claim indefinite. The term “increased” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claim does not even recite what the terms are meant to be “increased” in comparison to. Another issue is claim 38’s recitation of “(iv) confirming the expression of an ion channel or a monocarboxylic acid transporter associated with a corneal endothelial cell functional property in the functional human corneal endothelial cell”. It is unclear how expression of “ion channel” alone can lead to a functional property as virtually all cells express ion channels.
Claims 33, 38-39, and 52-55 remain rejected and new claims 56-59 are newly 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:
An in vitro method of manufacturing a functional human corneal endothelial cell capable of eliciting a human corneal function when infused into an anterior chamber of a human eye, the method comprising: proliferating and differentiating a human corneal endothelial progenitor cell in the presence of epidermal growth factor (EGF) at a concentration of less than 1ng/mL and in the presence of a ROCK inhibitor,
does not reasonably provide enablement for any method of doing so in the presence of any amount of EGF or in the complete absence of EGF. 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 these claims.
Claims 33, 38-39, and 52-55 remain rejected and new claims 56-59 are newly 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.
Amended claim 33 still allows for the complete absence of EGF while new claim 56 allows for the complete absence of EGF or the presence of any amount of EGF in the initial 7 days of each passage.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to a method of manufacturing a functional human corneal endothelial cell capable of eliciting a human corneal function when infused into an anterior chamber of a human eye. The method recites a single step of “proliferating and differentiating” a corneal endothelial cell. Hence, the nature of the invention is the manufacture of human corneal cells for cell therapy.
2) Scope of the invention. The scope of the invention is broad in that it encompasses a genus of methods for the manufacture of human corneal endothelial cells (HCEC) comprising what appears to be a step of culturing in media. Although this is not explicitly included, one can surmise that this is a necessary step. The culturing has a goal of proliferating and differentiating a human corneal endothelial progenitor cell with the only requirement being the presumed culturing is either in the absence or the presence in a concentration of less than 1ng/mL of epidermal growth factor (EGF), or in the presence of any amount of EGF for the first 7 days of “each passage”. The claims require functions of the HCECs produced through the method in requiring that they be “capable of eliciting a human corneal function when infused into an anterior chamber of a human eye” (claim 33), and have “a corneal endothelial cell functional property” (claim 38). Claim 38 connects presence of an ion channel to the recited function while claim 33 does not disclose any such structure/function relationship. Further, although a structure is given for the recited function in claim 38, there still exists an insufficient structure/function relationship between them as will be discussed below. Further, all of the properties claimed in claim 38 require only “confirming”, by any means, the presence or absence of some property of the cells. This is very broad as there is no required active step to be performed for the confirming and, consequently, the claim encompasses any possible known or unknown methods for carrying out the “confirming” (see 112(b) rejection above).
3) Number of working examples and guidance. The specification generically references “cell growth factors” and does not limit the phrase “cell growth factor” to the examples given (the examples including EGF, FGF, insulin-like growth factor (IGF), and transforming growth factor (TGF)) ([0264]). The working examples teach two in vitro culture methods utilizing a DMEMHG basal medium supplemented with fetal bovine serum (FBS) (Examples 1 and 2, [0444], and [0453]). In these examples, human subjects were used as the source for the corneal cells and the examples merely detail the donors and the “endothelial cell density” of the corneas ([0441], [0451]). These examples also refer to the presence or “absence” of EGF in the culture conditions along with testing conditions like the addition of Y27632, SB203580, and ascorbic acid ([0442]-[0443], and [0452]-[0453]). In both examples, the ROCK inhibitor is present continuously (denoted as Y+). Successive working examples merely reference the culture conditions from examples 1 and 2 and evaluate characteristics of the cells produced under each condition (anything to note about the characteristics) ([0462], [0458]-[0668]). No working example is provided which infuses the HCECs “to the anterior chamber of the human eye”. No working example is provided which supplies any amount of EGF for “the initial 7 days of each passage” as claimed in new claim 56.
4) State of the art. The instant inventors teach the state of the art at the time of filing (Toda, et al. Investigative ophthalmology & visual science 58.4 (2017): 2011-2020., hereinafter “Toda”). The proliferative potential of human corneal endothelial cells (HCECs) is limited and pathologically irreversible damage to the corneal endothelium leads to corneal endothelial dysfunction and the loss of corneal opacity (Toda, page 2011, first paragraph). Maintaining HCECs ex vivo for a long period of time is extremely difficult and repeated passages of the cells leads to cell-state transition (CST) into a senescence phenotype, epithelial-mesenchymal transition (EMT), and fibroblastic cell morphology (Toda, same paragraph). Because of these challenges, corneal transplantation is the only available therapeutic pathway for humans with corneal endothelial damage (Toda, same paragraph). Toda teaches the lack of standardized culture methods for HCECs, teaches a subpopulation of HCECs from primary heterogenous culture as the most suitable “effector” cell population for clinical applications in cell infusion in the anterior chamber, and teaches “detailed culture conditions” to reproducibly culture HCECs with a higher proportion of the identified subpopulation (Toda, pages 2011-2012, remainder of the introduction). Toda teaches the detailed method for culturing the HCECs which included isolation of HCECs from the Descemet’s membranes, the culture of HCECs in OpiMEM-1 basal medium supplemented with 8% FBS, 5ng/mL EGF, 20μg/mL ascorbic acid, 200mg/mL calcium chloride, 0.08% chondroitin sulfate, and 50 μg/mL gentamycin (Toda, “Cell Culture of HCECs”). Toda teaches that to reproducibly generate HCECs for cell therapy applications, continuous presence of the ROCK inhibitor, Y27632, and the absence of a selective inhibitor of TGF-β receptor is recommended (Toda, page 2016, first paragraph).
The instant invention appears to expand on the prior work of the instant inventors by testing even lower concentrations of EGF down to the “absence” of EGF and leaving out MSC-conditioned medium (See “Number of working examples and guidance” above). However, in every other respect, the methods appear to be the same except that the method instantly claimed is significantly broader in scope (encompassing presence or absence of EGF).
The art for producing corneal endothelial cells for cell therapy is unpredictable insofar as Toda teaches that the proliferative potential of human corneal endothelial cells (HCECs) is limited (Toda, page 2011, first paragraph), that maintaining HCECs ex vivo for a long period of time is extremely difficult and repeated passages of the cells leads to cell-state transition (CST) into a senescence phenotype, epithelial-mesenchymal transition (EMT), and fibroblastic cell morphology (Toda, same paragraph), that corneal transplantation is the only available therapeutic pathway for humans with corneal endothelial damage (Toda, same paragraph), that there is a lack of standardized culture methods for HCECs (Toda, pages 2011-2012, remainder of the introduction), and teaches a specific and detailed method for culturing the HCECs for therapeutic applications (Toda, “Cell Culture of HCECs”). Toda also teaches that to reproducibly generate HCECs for cell therapy applications, continuous presence of the ROCK inhibitor, Y27632, and the absence of a selective inhibitor of TGF-β receptor is recommended (Toda, page 2016, first paragraph).
Thus, at least at the time of Toda’s publication, the art for producing HCECs for cell therapy used a specific medium supplemented with FBS, 5ng/mL EGF, and the ROCK inhibitor, Y27632 to overcome art-recognized challenges in the area of HCEC culture for cell therapy applications.
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In a more recent publication by the instant inventors, the in vitro data discussed above was put to the test in a clinical trial (Kinoshita, et al. New England Journal of Medicine 378.11 (2018): 995-1003., hereinafter “Kinoshita”). Kinoshita teaches a method of culturing HCECs that is identical to that of Toda with the added specification that the medium contains 10μM Y27632 (See Kinoshita (2018)(Supplement), pages 6-7, last partial and first partial paragraphs respectively). Kinoshita goes further by teaching the actual injection of the HCECs suspended in the same medium discussed above into the anterior chamber of the human eye (Kinoshita, page 997, “Surgical procedure and follow-up”).
Thus, Kinoshita confirms the unpredictability in the art at the time of filing evidenced by Toda, by confirming that the art for producing HCECs for cell therapy used a specific medium supplemented with FBS, 5ng/mL EGF, and the ROCK inhibitor, Y27632 to overcome art-recognized challenges in the area of HCEC culture for cell therapy applications.
5) Unpredictability of the art. The claims are drawn to a method of manufacturing HCEC with the goal of creating cells capable of treating corneal disorders. To this end, the large and vague scope of the claims exacerbate the unpredictability of the art. As a first issue, the method is limited to simply proliferating and differentiating a corneal endothelial progenitor in the absence or presence of less than 1ng/mL EGF or in the presence of any amount of EGF for the “initial 7 days of each passage”. Reading into the disclosure, this appears to be a process wherein the progenitor cells are cultured for differentiation into the HCEC. Considering the conditions presented in the claims, one must consider what is required and necessary for this process as the claims only require EGF that is either lacking or absent. The examples perform the methods in media comprising FBS. It was known as far back as at least 1986 that fetal bovine serum (FBS) contains various growth factors (Honegger, et al. Journal of Biological Chemistry 261.2 (1986): 569-575., hereinafter “Honegger”). Honegger teaches that the survival of most types of cells of vertebrates in vitro is dependent on serum growth factors, among them epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor (IGF) (Honegger, page 569, first paragraph). Honegger also teaches that FBS contains at least IGF (Honegger, Abstract). In fact, FBS is known to inherently possess a variety of growth factors including EGF (Mohamed et al. Blood research 55.1 (2020): 35., hereinafter “Mohamed”, Fig. 2). Thus, the skilled artisan at the time of filing understood that the addition of FBS necessarily encompasses the addition of growth factors and the fact that FBS comprises EGF is an inherent characteristic of the FBS itself.
Furthermore, the combined teachings of Toda, Kinoshita, and Honegger as presented above evidence unpredictability in the field of HCEC culture for cell therapy where there is a complete absence of any growth factor all-together. Quite the opposite, the methods of Toda and Kinoshita (instant inventors), require FBS as does the instant invention (See “Number of working examples and guidance” above), which the skilled artisan understands to encompass growth factors including EGF. Hence, the claims lack the necessary components demonstrated to differentiate progenitor cells into HCEC starting with media and while they indicate that EGF is absent or in low dose, the conditions as broadly claimed do not reflect those that lead to HCEC as set forth in both the instant disclosure (where FBS is required) and the art at the time of filing.
Secondly, the methods are shown without performing infusion of the cultured cells into an anterior chamber and hence there is no demonstration of properties attained through this culture process. Therefore, it is unclear how the HCECs produced through the method of claim 33 can be said to possess the functional property of being “capable of eliciting a human corneal function when infused into an anterior chamber of a human eye”. Where the working examples teach the assessment of “ion channel”, they teach that the culture of HCECs with Y27632 and no added EGF (“standard cells”) results in increased ATP1A1, AQP1, SLC4A11, NHE1, and SLC25A42 expression whereas culture of HCECs with Y27632, and 5ng/mL EGF (“non-standard cells”) results in no expression of ATP1A1, AQP1, SLC4A11, NHE1, or SLC25A42 ([0578] and [0590]). Applicants state that “it is understood that the expression of a functional protein leading to a corneal endothelial (cell) functional property leading to improvement on corneal opacity and hydrous edema, resulting in continuous and long-term retention of corneal endothelial tissue cell density and improvement on visual acuity, is observed in standard cells”. This is very unclear as it appears to be merely prophetic in its recitation and there is no description of what a functional protein even is. Even if it is presumed that “a functional protein” is ATP1A1, AQP1, SLC4A11, NHE1, or SLC25A42, it is not enough to merely state that the functional property is “observed”. As stated above, no working example is provided which infuses the HCECs “to the anterior chamber of the human eye” so how is the skilled artisan supposed to connect the “ion channel” claimed to the recited functional properties of the cells when said properties would require some actual application of said cells to be able to “observe”. It is noted that the “ion channel” discussion in the example just discussed is at odds with the instantly claimed “EGF for no more than the initial 7 days of each passage” because said working example teaches that HCECs produced with 5ng/mL EGF expressed no ion channels and therefore do not have the functional property. How much less than 1ng/mL must the concentration of EGF be in order to produce HCECs with increased ion channel expression and consequently the recited functional properties (the skilled artisan would understand the distance between 1ng/mL and 0ng/mL to be large when the disclosed response is presence or complete absence of the morphological characteristic). The working examples do not teach any other “growth factors” besides EGF, nor do they teach any other culture medium besides DMDMHG supplemented with FBS. Thus, the working examples do not teach any method at all in which cells are cultured in the complete absence of EGF.
Furthermore, the relationship of enablement with the requirement for written description is acknowledged by the MPEP. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. The MPEP teaches, "However, claims reading on significant numbers of inoperative embodiments would render claims non- enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative. Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298,302 (CCPA 1971). (see MPEP 2164.08(b). In this case, the following issues add up to a significant number of inoperative embodiments such that undue experimentation would have been required.
The claims encompasses a genus of methods for the manufacture of human corneal endothelial cells from human corneal endothelial progenitor cells with the only requirement being either the absence or the presence in a concentration of less than 1ng/mL of EGF or the presence of any amount of EGF for the initial 7 days of each passage wherein the HCECs produced are “capable of eliciting a human corneal function when infused into an anterior chamber of a human eye”. The genus of methods encompasses methods lacking any growth factor at all as well as methods using any amount of EGF so long as it is used in the initial 7 days of each passage. Toda, Kinoshita and Konegger teach that methods for producing HCECs for cell therapy applications are very particular, always including at least a small amount of growth factors. A method here would at least be incompatible with a lack of growth factors all together insofar as the claims encompass an absence of growth factors entirely and the skilled artisan would understand the survival of most types of cells of vertebrates is dependent on serum growth factors, among them epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor (IGF) (Honegger, page 569, first paragraph). Further, owing to the unpredictability of the art, the skilled artisan would understand the genera of methods claimed to be so vast as to encompass many methods that have not been explored for their production of cells possessing the claimed functional characteristics.
Notably, each culture method taught in the working examples appears to require the addition of Y27632 from the very start and continuously throughout the culture (a ROCK inhibitor denoted as “Y”). None of the working examples appear to present a culture method without “Y” and, according to the provided drawings, a ROCK inhibitor appears to function to force the cells to differentiate into “differentiated mature cells” while culture without a ROCK inhibitor appears to induce “differentiated mature cells” to “dedifferentiate” into “proliferative undifferentiated cells” (Fig. 4). The working examples teach no method where Y is left out to allow for dedifferentiation, then added in a separate step to produce the HCECs (as broadly encompassed by claim 55).
6) Amount of Experimentation Required. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. The invention recites use of a broad group of culture conditions, and cell types. Given the unpredictability of the art of HCEC culture for cell therapy, the developed state of the art with regard to only a specific set of culture conditions taught to produce HCECs for cell therapy, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.
Consequently, the art at the time of filing when combined with the limited working examples provided by Applicant, shows that the skilled artisan at the time the invention was made would have had no basis to reasonably predict the manufacture of human corneal endothelial cells in vitro, comprising the proliferation and differentiation of a human corneal endothelial progenitor cell with the only requirement being either the absence of any growth factors at all or the presence in a concentration of less than 1ng/mL of EGF or the presence of any amount of EGF for the first 7 days of each passage given the lack of details necessary to identify culture conditions for producing HCECs meeting the necessary functions. Though not controlling, the limited working examples, are, nevertheless, a factor to be considered in a case involving both physiological activity and an undeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
When one is unable to envision the detailed steps of a method for production of a field-recognized difficult to produce cell type for cell therapy applications, such as a method for producing HCECs, so as to distinguish it from other methods, conception has not been achieved until reduction to practice has occurred.
As discussed above, predictability of methods for producing HCECs for cell therapy applications requires a specific knowledge of and guidance with regard to which components to include in a medium and the particular conditions and cell types to start with which continue to be difficult to identify outside of very specific medium, conditions, and cell types taught in the art at the time of filing. It is this specific guidance that applicants do not provide. While the art teaches specific methods, such teachings will not reduce the burden of undue experimentation on skilled artisans at arriving at the claimed invention as it is broadly claimed. Further, and as stated above, the claimed invention is not supported by a sufficient written description which would lead the skilled artisan to believe that the Applicant had possession of the claimed invention.
Response to Arguments
Applicant argues that “the amended claims fall squarely within this enabled scope acknowledged by the Office” (Remarks, page 12), and “the amended claims specifically recite the growth factor to be EGF and recite either its absence or a concentration of less than 1ng/mL, which is well within the scope that the Office acknowledged as enabled (less than 5ng/mL)” (Remarks, page 13). This argument has been fully considered but has not been found persuasive for the following reasons.
First, the Office did not acknowledge what Applicant asserts here. The identified scope in the non-final rejection mailed 25 November, 2025 never conceded that Applicant could have a complete absence of EGF. Second, this was one of the primary issues under both lack of enablement and lack of written description. Instead of amending the claims to require the presence of EGF, Applicant’s have instead opted to assert that such an amendment was never required without actually addressing the specific points raised in the prior rejection (one such point being that the art at the time of filing as well as the instant working examples all require FBS which the art at the time of filing evidences as possessing EGF). In addition, the amended claims allow for the complete absence of all growth factors (a condition which is an impossibility considering the required addition of FBS to the media of the art at the time of filing and the instant inventors). Still further, Applicants have added new claim 56 which allows for any amount of EGF to be added so long as it is in the first 7 days of “each passage”. Nowhere in the specification is there support for an indication that such a method works to produce cells having the functional characteristics claimed and the art at the time of filing does not teach as much either. Accordingly, this argument has been fully considered but has not been found to be persuasive.
Applicant also argues that the “specification builds upon and improves” the prior work of Toda “by demonstrating that even lower concentrations of EGF, down to and including the complete absence of EGF…yields superior results in producing functional human corneal endothelial cells” (Remarks, page 14). This argument has been fully considered but has not been found persuasive for the following reasons.
Applicant has not provided any working example which infuses cells into the anterior chamber of the human eye. Thus, it is unclear how the instant specification actually builds upon the prior work of Toda, since the specific cells produced through the method of Toda were shown to possess functional characteristics following such an infusion in the Honeggar publication (discussed in the above rejection), while the instant specification did not show as much. Rather, the instant specification relies on broad prophetic assertions to get to the recited functional properties while demonstrating only the production of cells without any actual infusion. In addition, the methods of the working examples all use FBS which has been shown to possess EGF. Applicant again ignores this fact with their arguments. Accordingly, this argument has been fully considered but has not been found to be persuasive.
Applicant also argues that skilled artisans following the instant disclosure would at most require only routine experimentation (Remarks, page 14). This argument has been fully considered but has not been found persuasive.
Again, Applicant ignores the fact that they are claiming a method of producing cells with a very specific functional property (capable of eliciting a human corneal function when infused into an anterior chamber of a human eye) produced in the complete absence of EGF while the art at the time of filing teaches this possibility only with very specific culture conditions which include 5ng/mL EGF and FBS. The working examples all use media comprising FBS (which contains EGF) and there is no working example at all which infuses any cells into any anterior chamber of any eye at all. Applicant asserts that they do not have to do any actual infusion because “a corneal endothelial functional property can be judged or determined by using a surrogate marker as an indicator” (Remarks, page 15). One such “surrogate marker” is the mere expression of an ion channel. Thus, Applicant’s argument amounts to an argument that any cell can be capable of eliciting a human corneal endothelial cell functional property so long as it expresses an ion channel (which virtually all cells do). Even ascribing more specificity to Applicant’s argument by applying human corneal endothelial progenitor cells and the methods claimed, it simply cannot be so that the mere expression of an ion channel suffices to predict cell functional properties when those cells are infused into an eye. Virtually any method which cultures corneal endothelial progenitor cells, so long as cells are produced (no matter what those actual cells are) will produce cells with ion channels. Accordingly, this argument has been fully considered but has not been found to be persuasive.
Applicant also argues against the written description portion of the above rejection by arguing that a proper written description rejection has not been made and that the Office has conflated the written description and enablement requirements (Remarks, page 16). This argument has been fully considered but has not been found persuasive for the following reasons.
First, Applicant cites to In re Oetiker, 977 F.2d 1443 (Fed. Cir. 1992) in support of the assertion that “a rejection for failure to comply with the written description requirement must be supported by its own analysis and factual basis, separate from any enablement rejection”. Contrary to Applicant’s assertion, In re Oetiker says nothing of the relationship between the written description and enablement requirements under 35 U.S.C. 112(a). Applicant correctly notes that the holding of In re Oetiker was that the USPTO bears the initial burden of establishing a prima facie case of unpatentability. However, this footnote is a distinct proposition from the factual assertion which it supports.
Second, a prima facie case of lack of written description had been established in the non-final rejection mailed 25 November, 2026 and the Examiner did not rely on “boilerplate” alone as Applicant asserts. While the written description and enablement requirements of 35 USC 112, 1st para. are separable, in this instance the facts and issues are so interrelated that the specification fails to meet both requirements for the genus of methods claimed for essentially the same reasons. As to enablement, one cannot make what one cannot conceive. First, the scope of the invention is extremely broad. The claims lack enablement due to excessively broad scope pertaining to the genus of methods for producing HCECs encompassed. Functional properties are required of the cells by way of their being capable of eliciting a human corneal function when infused into an anterior chamber of a human eye. However, as set forth in the above rejection, the specification does not provide adequate guidance of the structural requirements required for these functional properties and the methods claimed broadly encompass the complete lack of EGF or the presence of any amount of EGF for the first 7 days of each passage (as amended) while the art at the time of filing and the instant application demonstrate that cells are only able to be made with the recited functional properties if they are cultured in the presence of FBS which itself contains EGF. Hence the claims also lack Written Description such that a person of skill in the art would not recognize that Applicants were in possession of the genus of methods claimed. Accordingly, this argument has been fully considered but has not been found to be persuasive.
Applicant also reiterates prior arguments presented in support of enablement for support of written description. These arguments are not found to be persuasive for the same reasons discussed above.
Double Patenting
A rejection based on double patenting of the "same invention" type finds its support in the language of 35 U.S.C. 101 which states that "whoever invents or discovers any new and useful process ... may obtain a patent therefor ..." (Emphasis added). Thus, the term "same invention," in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957); and In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970).
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970);and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
The safe harbor for non-statutory double patenting only applies for applications filed as divisional applications. Because all sets of claims are drawn to methods of making HCECs, HCECs, and methods of using HCECs, the claims are related under the non-statutory double patenting statute. None of the U.S. Application Nos. 17/074,912, 16/078,002, or 19/259,859 have been filed as divisional applications of the present Application.
Claims 33, 38-39, and 52-55 remain provisionally rejected and claims 56-59 are newly provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 31-32, 35-36, 39, 41-42, 54, 60, 62, and 69-88 of copending Application No. 16/078,002, claims 31-33, 38, 40, 42-49, 52-54, 57-59, and 61-71 of copending Application No. 17/074,912. The provisional rejection of claims 33, 35, 37-39, and 52-55 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims claims 31-60 of copending Application 19/259,859 is rendered moot by the express abandonment of the copending application. This rejection has been modified as necessitated by Applicant’s amendments to the claims in this and each respective copending application.
The instant claims are drawn to a method of making the cells of copending Application No. 16/078,002 which are claimed in methods of treatment in copending Application No. 17/074,912. The specification of the copending applications disclose identical methods of making for the claimed HCECs as that recited in the instant claims.
Note that MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for ODP rejections.
In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. The court in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
Independent claim 31 of copending application No. 16/078,002 is directed to “A population of functional cultured human corneal endothelial cells (cHCECs) that are capable of eliciting a human corneal endothelial functional property when administered into an anterior chamber of a human eye, wherein 75% or more of the cells of the population have a cell surface antigen phenotype that is CD 166 positive, CD 105 negative to CD105 weakly positive, CD24 negative, and CD44 negative to CD44 weakly positive.”
Independent claim 31 of copending application No. 17/074,912 is directed to “A method for treating a corneal endothelial dysfunction or disease, comprising administering into an anterior chamber of a human eye, an effective amount of a population of functional cultured human corneal endothelial cells (cHCECs) capable of eliciting a human corneal endothelial functional property when administered into an anterior chamber of a human eye, and wherein 75% or more of the administered cells have a cell surface antigen phenotype that is simultaneously CD166 positive, CD105 negative to CD105 weakly positive, CD24 negative, and CD44 negative to CD44 weakly positive.”
Independent claim 33 of the instant Application is directed to “An in vitro method of manufacturing a functional human corneal endothelial cell capable of eliciting a human corneal function when infused into an anterior chamber of a human eye, the method comprising: proliferating and differentiating a corneal endothelial progenitor cell (i) in the presence of a Rho-associated protein kinase (ROCK) inhibitor and (ii) in the absence of epidermal growth factor (EGF) or in the presence of EGF at a concentration of less than 1ng/mL, thereby obtaining the functional human corneal endothelial cell.”
Instant claim 33 is directed to a method of making a cell whereas copending claim 31 of each respective copending application is directed to a cell or a method of using that cell. Double-patenting rejections of claims to methods and compositions based on a claimed method of use are proper. This rejection is necessitated by the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc. v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Copending application No. 16/078,002 discloses a method of manufacturing a human functional corneal endothelial cell capable of eliciting a human corneal endothelial functional property when infused into an anterior chamber of a human eye comprising a step of culturing to mature and differentiate a corneal tissue-derived cell or a corneal endothelial progenitor cell (Copending specification, page 11, (Item B1)). While the copending application teaches a medium comprising 5ng/mL EGF, it more generically teaches embodiments of the method using a medium without any reference to growth factor (Copending specification, page 11, (Item B1), [0299]). Even if the specific method with 5ng/mL were to be accepted as the only method disclosed by the copending applications (which it is not), it is noted that, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). Modulating the level of EGF, especially by as little as 4ng/mL to fall within the scope of instant claim 33 would be routine optimization for a person having ordinary skill in the art of cell culture. Since, the other copending application is a continuation of 16/078,002, all copending applications share the same supporting disclosure. Therefore, the method of making HCECs instantly claimed would have been obvious to a person having ordinary skill in the art in view of copending claims 31-32, 35-36, 39, 41-42, 54, 60, 62, and 69-88 of copending Application No. 16/078,002, and claims 31-33, 38, 40, 42-49, 52-54, 57-59, and 61-71 of copending Application No. 17/074,912 with their accompanying, shared disclosure.
Response to Arguments
Applicant argues against the use of the supporting disclosure of the copending applications to support the provisional non statutory double patenting rejections and relies on the copending applications not having claimed any methods of making to support their argument (Remarks, page 20). Applicant also argues that the disclosures do not teach the exact concentration of EGF claimed in this application and “the mere absence of a reference to any growth factor in a single disclosure item cannot reasonably be interpreted as an affirmative teaching or disclosure of the absence of EGF or the use of EGF at concentrations below 1 ng/mL” (Remarks, page 21). Applicant also argues against the alternative perspective that lowering EGF concentration would represent routine optimization in the context of the copending disclosure and supports this argument with a statement of “surprising and unexpected advantages” associated with using no or reduced EGF (Remarks, page 21). These arguments have been fully considered but have not been found persuasive for the following reasons:
First, MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for ODP rejections, and the above rejection which relies on portions of the supporting disclosure is necessitated by the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc. v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application. Applicant has not discussed or argued against the Pfizer decision and as far as the Office is aware, Pfizer is good law. In the instant case, Applicant is claiming a method of making functional human corneal endothelial cells capable of eliciting a human corneal function when infused into an anterior chamber of a human eye. The copending Applications are also drawn to cells having the identical structural and functional characteristics. Therefore, there is no patentable distinction between the products disclosed in this application and those disclosed in the copending applications and the respective methods of making and using said products similarly lack a patentable distinction where they are all drawn to the same product. This is not a divisional application.
Further, this is not a case of “mere absence of a reference to any growth factor in a single disclosure item” as Applicant contends. Rather, page 11 of the shared disclosure of the copending applications is full of discussion for the method of making the cells having the exact same structural and functional characteristics as the instant Application (see 16/078,002 Specification page 11). Indeed, page 11 specifically discusses the absence of a growth factor (TGFβ) and the presence of a ROCK inhibitor (item B7). Thus, the copending disclosure plainly encompasses embodiments for the method of making cells having the exact same structural and functional characteristic wherein the method does not utilize EGF.
Lastly, Applicant’s argument in the alternative against routine optimization relies on various potential improvements to the process of making but not to the product made (which again has the exact same structural and functional characteristics to the product disclosed in the copending applications). Thus, it is unclear how any potential superior or unexpected result with respect to culturing the cells can have any meaningful impact on a method of using said cells when the cells themselves are the same. Still further, evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential). See also MPEP 716.02e.
Accordingly, Applicant’s arguments have been fully considered but have not been found to be persuasive.
New Rejections Necessitated by Applicant’s Amendments to the Claims
Claim Rejections - 35 USC § 112
New claims 56-59 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 claims contain 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. This is a new matter rejection.
New claim 56 recites “comprises EGF for no more than the initial 7 days of each passage”. However, this is not supported by the specification. The MPEP teaches, “New or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads). (see e.g. MPEP 2105).
In the instant case, nowhere in the specification or claims as originally filed is there any teaching to use a medium which comprises EGF only for the initial 7 days of each passage. Where lengths of a passage are taught, it appears to be variable and without regard to EGF (Table 7). In addition, there is no description of how one adds a component to a cell culture then guarantees its absolute removal after some length of time. The specification states that it is possible to have addition only at the initial stage of culture “(e.g. within 7 days, etc.)”. However, this stops well short of a description of a method in which EGF specifically is present only for the initial 7 days of each passage.
Therefore, the new limitation added by way of claim 56 is new matter and a skilled artisan would not reasonably conclude that Applicant had possession of such a method at the time of filing. Claims 57-59 all depend from and read on the new matter.
New claims 56-59 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
New claim 56 recites “comprises EGF for no more than the initial 7 days of each passage”. There is insufficient antecedent basis for this limitation in the claim. Nowhere in the method is a passage let alone multiple passages required. Thus, it is unclear what “each passage” in the wherein clause is referring back to in the method comprising steps (a) and (b). Accordingly, a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought. Claims 57-59 are further rejected for their dependency on a rejected base claim.
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 BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA MARVICH/Primary Examiner, Art Unit 1634
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