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
This Office Action is a response to Applicant’s Amendment and Remarks filed October 6, 2025.
Claims 1 and 22 have been amended.
Claims 1, 3 and 20-22 are pending in the instant application.
Accordingly, claims 1, 3 and 20-22 have been examined on the merits as detailed below:
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112
In the previous Office Action mailed May 5, 2025, claims 1, 3 and 20-22 were 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. This rejection is maintained for the reasons of record set forth in the previous Office Action mailed May 5, 2025.
Response to Arguments
In response to this rejection, Applicants traverse and argue that the application indeed describes the use of a RNA-guided nuclease, including a working example where a CRISPR-based knockout (KO) of LINC01614 is described in detail. Applicants point the Examiner to Example 2 of the instant application at pages 55-56 and Figure 7. Also, Applicants submit that the Federal Circuit has confirmed that "working examples or an actual reduction to practice are not necessary to satisfy the written description requirement." Further, Applicants submit that one of skill in the art at the time of filing, would understand that achieving a successful gene-editing experiment is within the capabilities of almost every biological lab. Applicants point the Examiner to L. Thorne, “Choosing the Right sgRNA for Your CRISPR Experiments” September 8, 2020. Accordingly, Applicant submits that the written description requirement has been satisfied for the claimed subject matter and withdrawal of the instant rejection is requested.
Applicant’s arguments have been considered by the Examiner, however they are not found persuasive. When referring to Example 2 of the instant application at pages 55-56 and Figure 7 as directed by Applicant, the Example discloses that using a Lenti-CRISPR v2-Blast carrying Blasticidin selection gene and guide RNA for LINC01614 CRISPR knockout, LINC01614 KO cells were confirmed to lack LINC01614 expression. The Example also teaches that LINC01614-KO adipose-derived stromal cells (ASC) had dramatically reduced COL11A1 expression (FIG. 7), indicating that LINC01614 controls the expression of COL11A1. Example 2 does not support an RNA-guided nuclease that inhibits or eliminates the expression, activity or function of SFRP4 as claimed.
While a working example is not necessary to satisfy the written description requirement, showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”). The specification does not provide guidance regarding the structure of any RNA-guided nuclease that inhibits or eliminates the expression, activity or function of SFRP4 (emphasis added). No CRISPR-based knockout of SFRP4 is shown. Only LINC01614 CRISPR KO with reduced COL11A1 expression is disclosed. There is no guidance whether there is any common structure that is shared by an RNA-guided nuclease that inhibits or eliminates the expression, activity or function of SFRP4 as claimed. The specification does not support possession of the entire genus of RNA-guided nucleases that inhibits or eliminates the expression, activity or function of SFRP4 as encompassed by the claimed invention. Applicant is reminded that a disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed by him.
Regarding Applicant’s argument that achieving a successful gene-editing experiment is within the capabilities of almost every biological lab, the Examiner would like to point Applicant to University of Rochester v. G.D. Searle & Co., 68 USPQ2d 1424 (W.D.N.Y. 2003). At issue was a patent directed to method for inhibiting prostaglandin (PGHS-2) synthesis in a patient using an unspecified compound. The District Court of Western New York evaluated the level of disclosure required to satisfy the written description. In their decision (which was later affirmed by the Court of Appeals for the Federal Circuit), the District Court wrote, “The real issue here is simply whether a written description of a claimed method of treatment is adequate where a compound that is necessary to practice that method is described only in terms of its function, and where the only means provided for finding such a compound is essentially a trial-and-error process.” The patent in Rochester does no more than describe the desired function of the compound called for, and it contains no information by which a person of ordinary skill in the art would understand that the inventors possessed the claimed invention. At best, it simply indicates that one should run tests on a wide spectrum of compounds in the hope that at least one of them will work. The specification of the patent in Rochester states that the invention comprises, inter alia, “assays for screening compounds, including peptides, polynucleotides, and small organic molecules to identify those that inhibit the expression or activity of the PGHS-2 gene product; and methods of treating diseases characterized by aberrant PGHS-2 activity using such compounds.” Nowhere, however, does it specify which “peptides, polynucleotides, and small organic molecules” have the desired characteristic of selectively inhibiting PGHS-2.
The Rochester court cited the CAFC in Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 1316 (63 U.S.P.Q.2d 1609), which adopted the standard set forth in the Patent and Trademark Office (“PTO”) Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1 “Written Description” Requirement (“Guidelines”), 66 Fed. Reg. 1099 (Jan. 5, 2001), which state that the written description requirement can be met by “showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics,” including, inter alia, “functional characteristics when coupled with a known or disclosed correlation between function and structure ... .” Enzo, 296 F.3d at 1324-25 (quoting Guidelines, 66 Fed. Reg. at 1106 (emphasis added)).
The fact pattern in the instant case is similar to that in Rochester. The specification does not provide sufficient descriptive support for an RNA-guided nucleases that inhibits or eliminates the expression, activity or function of SFRP4 as claimed. No CRISPR-based knockout of SFRP4 is shown. Only guidance for LINC01614 CRISPR KO with reduced COL11A1 expression is disclosed. See Example 2 and Figure 7.
Further, The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species in examples that encompass the genus. (MPEP § 2163). The specification does not provide any descriptive support for an RNA-guided nucleases that inhibits or eliminates the expression, activity or function of SFRP4 as claimed. No CRISPR-based knockout of SFRP4 is shown. Applicant in not in possession of the claimed genus.
Regarding L. throe (referenced article attached with this Office Action), the editorial article actually supports the present rejection for lack of written description since relevant identifying characteristics for CRISPR gene editing (e.g. sgRNA which efficiently recruit the Cas9 endonuclease to the target site to introduce a double-strand break, while at the same time display minimal off-target activity) are completely lacking in the instant application.
For all these reasons, it stands that the claims remain rejected under 35 U.S.C. 112 as failing to comply with the written description requirement.
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In the previous Office Action mailed May 5, 2025, claims 1, 3 and 20-22 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. This rejection is maintained for the reasons of record set forth in the previous Office Action mailed May 5, 2025.
Response to Arguments
In response to this rejection, Applicants traverse and argue that CRISPR technology is not so unpredictable as to require undue experimentation to practice the claimed method. Applicants submit that the citations the Examiner relied upon regarding CRISPR unpredictability are outdated and therefore do not support the Examiner’s position. Further, Applicants argue that one of skill would be able to practice the claimed invention without resorting to undue experimentation. Applicants point the Examiner to Amgen V. Hoechst Marion Roussel, 314 F.3d 1313, 1336 (Fed. Cir. 2003); Amgen v Sanofi, 598 U.S. 594, 611 (2023); and Thorne, “Choosing the Right sgRNA for Your CRISPR Experiments”, September 8, 2020. Applicants also point the Examiner to arguments and supposedly “post-filing experiments” in the § 1.132 Declaration filed October 6, 2025 to support their argument.
For these reasons, Applicants submits that the claimed subject matter is indeed enabled by the application as filed when taken in light of the knowledge of one of ordinary skill in the art. Accordingly, Applicant respectfully requests withdrawal of the instant rejection.
Applicant’s § 1.132 Declaration filed October 6, 2025 has been fully considered but it is not persuasive. Additionally, Applicant’s arguments have been considered by the Examiner, however they are not found persuasive since the Examiner maintains that the enablement rejection is appropriate since there is no guidance regarding how to make and use the RNA-guided nuclease that can inhibit or eliminate the expression, activity or function of SFRP4.
Regarding L. Thorne (referenced article attached with this Office Action), the editorial article actually supports the present rejection for lack of enablement since it details the challenges of using CRISPR technology in a subject and highlights that embarking on a CRISPR experiment is not a trivial undertaking, requiring significant optimization, which can be time consuming and labor intensive. According to L. Thorne, it has been estimated that a single CRISPR experiment takes on average 10 weeks to perform - and that’s assuming success on the first try, with experiments usually restarted around 7 times. Furthermore, L. Thorne are clear in detailing the key importance of predicting on-target activity; minimizing off-target effects; and choosing the best single guide (sgRNA) for successful CRISPR gene editing.
According to L. Thorne, “Good sgRNA design is key” (emphasis added). For example, there is significant variation in the cleavage efficiency of certain sgRNA, as well as potential for off-target activity. L. Thorne also disclose that it is good practice to include several different sgRNA per gene in your experiment to avoid having to start all over again if it turns out your chosen sgRNA is inefficient. Applicant is reminded that not a single species of RNA-guided nuclease that inhibits or eliminates the expression, activity or function of SFRP4 has been disclosed in the present application. For further explanation, see the maintained 35 USC § 112 rejection for written description supra.
There are many challenges associated with using CRISPR gene editing. Choosing the right gRNA sequence is arguably the most critical step in CRISPR as this is a complex process that requires careful consideration of various factors to achieve high on-target efficiency and specificity. See Doreen Ding, A Guide to Efficient CRISPR gRNA Design: Principles and Design Tools, April 25, 2024. Applicant is again reminded that not a single species of RNA-guided nuclease that inhibits or eliminates the expression, activity or function of SFRP4 has been disclosed in the present application.
The Examiner maintains that in order to practice the invention using the Specification and the state of the art as outlined above, the quantity of experimentation required to practice the invention as claimed would require the de novo determination of which RNA-guided nuclease inhibit or eliminate the expression, activity or function of SFRP4 resulting in reducing the transition of ASCs to COL11A1-expressing CAFs in a subject. As supported by the present Specification and art, such analysis is replete with trial and error experimentation. Such experimentation represents an inventive and unpredictable undertaking in itself, with each of the many intervening steps, not providing any guarantee of success. Given the art recognized unpredictability of the using CRISPR gene editing, this determination would not be routine and would require undue trial and error experimentation.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the Specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” The Wands Factors have been weighed and favor undue experimentation.
In view of the breadth of the claims, the lack of guidance, the unpredictability in the art, and the lack of working examples, the instant Specification is not found to be enabling for the method as claimed. It would require undue experimentation and making a substantial inventive contribution for the skilled artisan to discover how to make and/or use the claimed invention over its full scope.
For these reasons, it stands that the claims remain rejected under 35 U.S.C. 112 as lacking enablement.
NOTE: In their arguments filed October 6, 2025, Applicants point the Examiner to “post-filing experiments” in the § 1.132 Declaration filed October 6, 2025 to support their argument that the claims are fully enabled. The Examiner would like to note and make the record clear that not a single post-filing experiment is found or detailed in the § 1.132 Declaration filed October 6, 2025.
THIS ACTION IS MADE FINAL. 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.
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/TERRA C GIBBS/ Primary Examiner, Art Unit 1635