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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/23/2025 has been entered.
Application status
In response to the previous Office action, a Final rejection (mailed on 09/25/2025), Applicants filed a response and amendment received on 12/23/2025. Said amendment canceled Claims 20, 25, 27 and 29-32, amended Claims 18, and added claim 33. Thus, Claims 18, 21-23 and 33 are at issue and present for examination.
It is noted by the Examiner that Claims 1-17, 19, 24, 26 and 28 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention in the previous Office actions, a non-Final rejection (mailed on 03/20/2025).
Claim Objections
The previous objection of Claims 1-17, 19, 24 and 28 for containing an incorrect status identifier “(Previously Presented)” is withdrawn by virtue of Applicants’ amendment.
Claim Rejections - 35 U.S.C. § 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 previous rejection of Claims 18, 20-23, 25-27, 29 and 30 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ) for omitting elements is withdrawn by virtue of Applicants’ amendment.
Claims 18, 21-23 and 33 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.
Claims 18, with 21-23 and 33 dependent therefrom, are indefinite because it is unclear when the amount of the indicator substance measured from the ES cells is “equal” to that of the control cells as recited in claim 18, how this can be evaluated as having differentiated into retinal pigment epithelial cells when the amount of the adenosine is the same (italicized for added emphasis). Furthermore, even when the amount of the indicator substance is “greater than a predetermined threshold,” it is unclear how one can determine what the predetermined threshold is since this value can be any number, thereby rendering the claims indefinite.
Claim Rejections - 35 U.S.C. § 112(a)
The following is a quotation 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.
Claim 33 is 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.
Claim 33 recites that “the predetermined threshold is 2.8 or higher” which is new matter. None of the instant specification and drawings including Figure 6C under K supports the newly added claim language, and there is nothing in the specification which demonstrates how such the predetermined threshold of 2.8 or higher can be derived. For this reason, the newly added claim 33 is rejected under 112(a) as reciting new matter, and the inventor(s), failed to show that at the time the application was filed, applications had possession of the claimed invention.
Claims 18, 20-23, and 33 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of measuring adenosine in the culture supernatant of ES cells (see Figure 6C under K), does not reasonably provide enablement for a method for evaluating a differentiation state of ES cells in a step of inducing differentiation of embryonic stem cells (ES cells) into retinal pigment epithelial cells, comprising (1) a step of measuring an amount of an indicator substance present in a culture supernatant of ES cells, (2) a step of evaluating a state of cell differentiation from ES cells to retinal pigment epithelial cells based on a change in the amount of the indicator substance, and (3) a step of measuring an amount of the indicator substance in a culture supernatant of control cells whose state of cell differentiation is known, wherein in step (2), when a ratio of the amount of the indicator substance present in the culture supernatant of the ES cells to the amount of the indicator substance present in the culture supernatant of the control cells is equal to or greater than a predetermined threshold, the ES cells are evaluated as having differentiated into retinal pigment epithelial cells, and wherein the indicator substance is adenosine. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breath of the claims. The factors which have lead the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breath of the claims. Claims are drawn to a method for evaluating a differentiation state of ES cells in a step of inducing differentiation of embryonic stem cells (ES cells) into retinal pigment epithelial cells, comprising (1) a step of measuring an amount of an indicator substance present in a culture supernatant of ES cells, (2) a step of evaluating a state of cell differentiation from ES cells to retinal pigment epithelial cells based on a change in the amount of the indicator substance, and (3) a step of measuring an amount of the indicator substance in a culture supernatant of control cells whose state of cell differentiation is known, wherein in step (2), when a ratio of the amount of the indicator substance present in the culture supernatant of the ES cells to the amount of the indicator substance present in the culture supernatant of the control cells is equal to or greater than any predetermined threshold, the ES cells are evaluated as having differentiated into retinal pigment epithelial cells, and wherein the indicator substance is adenosine (italicized for added emphasis).
The amount of direction or guidance presented and the existence of working examples. The specification discloses a method of measuring the amount of adenosine (see Figure 6c under K). However, the specification fails to provide any clue as to how a correlation can be made between the amount of indicator substance, adenosine, which is present in a culture supernatant of ES cells, and the amount present in a culture supernatant of controls cells, especially when a ratio of the amount of the indicator substance present in the culture supernatant of the ES cells to the amount of the indicator substance present in the culture supernatant of the control cells can be equal to or greater than any predetermined threshold, which can be any value (italicized for added emphasis, also see above 112(b) rejection), in order to evaluate a state of cell differentiation from embryonic stem (ES) cells to retinal pigment epithelial (RPE) cells. What the minimum amount of increase in the amount of adenosine as represented by a predetermined threshold does one need to observe in the culture supernatant of ES cells in order to determine that the ES cells have fully differentiated into RPE cells? There is no guidance regarding how much greater the amount of adenosine, represented by a predetermined threshold which can be any value, must be present in the culture supernatant of ES cells compared to that of the control cells, and how such an increase in the measured amount can be correlated to the state of differentiation from ES cells into RPE cells (i.e., differentiation of 100% of ES cells into RPE cells). Furthermore, there is no guidance on how one can arrive at the predetermined threshold is 2.8 or higher as recited in claim 33 by looking at Figure 6c under K.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art.
According to Kamao et al. (Characterization of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Sheets Aiming for Clinical Application, Stem Cell Reports, Vol. 2, February 11, 2014, pp.205-218, see IDS), it was well-known to one of ordinary skill in the art in the relevant field of art that secretions of VEGF and pigment epithelium-derived factor (PEDF) are indicative of the differentiation state to RPE cells (see page 8315, left column, first paragraph and Figure 5J on page 8314).
Kamao et al. further teach that there is an unpredictability associated with using degree of pigmentation (dPG) in determining the state of differentiation to RPE cells as their time-dependent experiment did not exhibit a correlation between the dPG with VEGF and PEDF (compare Figure 5G to 5H on page 8314, which is discussed in page 8313, right column, last paragraph continued to page 8315)
Similarly, the measured amount of adenosine alone is highly unpredictable for one of ordinary skill in the art to conclude that 100% of the population of ES cells have indeed fully differentiated into RPE cells because there is no information in the relevant field of art that provides any clue as to how a correlation can be made between the amount of adenosine and the state of cell differentiation from embryonic stem (ES) cells to retinal pigment epithelial (RPE) cells.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of measuring adenosine present in a culture supernatant of ES cells were known in the art at the time of the invention, it was not routine in the art to monitor the level of adenosine for any length of time in the culture supernatant of ES cells in comparison to that of the control cells in order to make a conclusive correlation about the differentiation state of ES cells to RPE cells. In the absence of (1) a rational and predictable scheme for determining the differentiation state of ES cells to RPE cells, and/or (2) a correlation between the increased amount of adenosine level in the culture supernatant of ES cells compared to that of the control cells, and how such increase in the amount of adenosine is indicative of the state of differentiation from ES cells to RPE cells, one of skill in the art would have to perform undue experimentations.
Claim 33 is included in this rejection because even though claim 33 recites that the predetermined threshold is 2.8 or higher, there is no guidance in the instant specification even considering Figure 6c under K, as to how one of skill in the art can arrive at this predetermined threshold or what this predetermined threshold means. Furthermore, the instant specification does not provide a concrete evidence which shows that when the predetermined threshold is 2.8 or higher, the state of differentiation from ES cells to RPE cells is complete at 100% population of the cells.
Without such correlation between [1] the specific increase in the amount of adenosine, and [2] the percentage of differentiation observed from ES to RPE cells, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed methods.
Therefore, taken together with the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between the amount of adenosine and the differentiation state of ES cells to RPE cells, and the high degree of unpredictability of the prior art, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Applicants’ arguments:
Applicants argue that based on the amended claim 18, which recites that "when the ratio of the amount of the indicator substance... is equal to or greater than a predetermined threshold, the ES cells are evaluated as having differentiated into retinal pigment epithelial cells", the instant claims are enabled.
Examiner’s explanation:
Applicants’ arguments have been fully considered but are not deemed persuasive for the following reasons. The Examiner has basically provided why the instant claims as amended are rejected above. In addition, the high unpredictability associated with determining the state of differentiation from ES to RPE cells, any increase in the amount of adenosine from culture supernatant of ES cells to that of the control cells even according to Applicants’ own data in Figure 6c K is NOT associated with differentiation of ES cells to RPE cells since starting day 30, there are significant increase in the amount of adenosine, however, Applicants argue that according Example 3, it is only at day 42, Applicants begin to observe that some of the human ES cells have differentiated (italicized for added emphasis), which does not convey 100% differentiation into RPE cells from ES cells. Taken together, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention as it is highly unpredictable to determine conclusively the differentiation state of ES to RPE cells especially when it is based on a ratio of the amount of the indicator substance present in the culture supernatant of the ES cells to the amount of the indicator substance present in the culture supernatant of the control cells, which can be equal to or greater than any predetermined threshold (italicized for added emphasis).
Claim Rejections - 35 U.S.C. § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
The previous rejection of Claim 18 under 35 U.S.C. 102(a)(1) as being anticipated by CN108350480 A (published on 07/31/2018, see IDS) is withdrawn because said reference does not teach “adenosine” as the indicator substance.
Conclusion
Claims 18, 20-23 and 33 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656