DETAILED ACTION
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 .
Amendments
This action is in response to papers filed 21st May, 2026 in which claims 25-26, and 29-31 were amended with new limitations that are supported by the disclosure, claims 27-28 and 32-33 were canceled, and new claims 34-37 that are supported by the disclosure were added. All of the amendments have been thoroughly reviewed and entered.
Any rejection or objection not reiterated herein has been overcome by amendment.
However, new rejections are set forth that are applicable to the current claims. Applicant's remarks have been fully considered but are moot because they do not specifically address the new rejections.
Election/Restrictions
Applicant’s election without traverse of Group V (claims 25-33) drawn to a method of treating a subject by administering an inhibitor, in the reply filed on Dec 10, 2025 was previously acknowledged. New claims 34-37 are being added to elected Group V.
Additionally, Applicant’s election without traverse of the following Species:
I. LINC01679;
in the same reply was acknowledged.
Claims 14-24 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on Dec 10, 2025 and is made final.
Status of the Claims
Accordingly claims 25-26, 29-31, and 34-37 are being examined.
Priority
This application is a 371 of PCT/CN2021/097061 filed May 30th, 2021 and claims foreign priority to several foreign applications all filed May 31st, 2020. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copies have been received. The Examiner notes that an English language translation has been provided. The priority date of instant application is perfected and is May 31st, 2020.
Withdrawn Specification Objections
Trade name has been corrected with proper symbol following the term.
Abstract has been amended.
New Claim Objections
Claim 36 is objected to because of the following informalities: the inhibitor is … or zinc finger nucleases … the zinc finger nucleases programmed to target the LINCO1679 locus is awkward. Appropriate correction is required.
Claim Rejections - 35 USC § 112
Withdrawn Written Description Rejection
Applicants have amended claims 25-26, and 29-31 and canceled claims 27-28 and 32-33 to limit the inhibitor of LINC01679 to interference RNA or zinc finger nucleases programmed to target the LINC01679 locus. The amendment has overcome the written description rejection. The written description rejection of claims 27-28 and 32-33 is withdrawn.
Maintained and New Scope of Enablement Rejection
Claims 25-26 and 29-31 remain rejected and claims 34-37 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 inhibiting LINC01679 gene expression and inhibiting proliferation or migration in cells comprising administering an siRNA specific for LINC01679, does not reasonably provide enablement for the instant method of treating oral squamous cell carcinoma or inhibiting proliferation or migration in vivo. 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. This rejection has been rewritten to address amendments.
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.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
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.
Claim Interpretation
The following are recitations from independent claims 25 and 30:
claim 25
claim 30
A method
A method
for treating oral squamous cell carcinoma
for treating oral squamous cell carcinoma
comprising:
comprising:
administering to a subject a pharmaceutically effective amount of
administering to a subject a pharmaceutical composition,
an inhibitor of LINC01679, the inhibitor is interference RNA or zinc finger nucleases, the interference RNA comprises a sequence that is complementary to the LINC01679 transcript, and the zinc finger nucleases are programmed to target the LINC01679 locus.
the pharmaceutical composition comprises an inhibitor of LINC01679 and a pharmaceutically acceptable carrier, the inhibitor is interference RNA or zinc finger nucleases, the interference RNA comprises a sequence that is complementary to the LINC01679 transcript, and the zinc finger nucleases are programmed to target the LINC01679 locus.
New claim 36 is similar in scope except the preamble recites, “A method for inhibiting proliferation or migration of oral squamous cell carcinoma cells, comprising …”. Thus, claims 25, 30, and 36 have the same active step of administering and are being given the broadest reasonable interpretation which is: in vitro and in vivo treatment of oral squamous cell carcinoma comprising administering either an interference RNA inhibitor of LINC01679 or zinc finger nucleases programmed to target the LINC01679 locus.
Applicants disclose in pg. 6: the subject is a human.
The Nature of the Invention
The invention is drawn to a method of treating oral squamous cell carcinoma in a subject in need thereof.
Breadth of the Claims
Instant claims encompass:
“treating” or inhibiting proliferation or migration
The specification provides no definition/description of the term “treating”.
“a subject”
This encompasses all possible mammalian subjects preferably, human mammals.
“administering”
This encompasses all ways of administering which includes but is not necessarily limited to:
All routes of administration including topical, injection, inhalation, and others.
a “LINC01679 inhibitor” that decreases levels of LINC01679 mRNA anywhere in the subject.
Determining a pharmaceutically effective amount of an inhibitor (claim 25).
These encompass:
All possible interference RNA inhibitors or the zinc finger nucleases are programmed to target the LINCO1679 locus that inhibit the lncRNA, LINC01679, as pharmaceutical agents, that decrease LINC01679 mRNA or protein by acting directly on LINC01679 mRNA or locus and result in an decrease of LINC01679 mRNA;
All possible vectors of all possible types including the above mentioned agents that include viral and non-viral vectors of all types.
Thus, the breath of claims is vast.
The level of ordinary skill in the art
An ordinary artisan in the area of drug development would have experience in screening chemical compounds for particular activities. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of biological systems.
Determining how a particular chemical will impact the body is not routine. See Knowledge in the Art section.
Thus, the level of ordinary skill in the art of treating cancer is high, as an ordinary artisan in this art needs specialized knowledge of the complex nature of the biology of cancer.
Direction or Guidance Presented
The focus here will be on elements for which some written description is provided.
The interference RNA
At the outset, it is noted that the claims do not recite a specific interference RNA (claims 25-26 and 30-31), but rather refer to the broad genus of interference RNA inhibitors or the zinc finger nucleases are programmed to target the LINCO1679 locus that inhibit the lncRNA, LINC01679.
The instant claims embrace contacting any biological system via any means of delivery with any antisense oligomer so that LINC01679 levels are decreased.
Table 3 provides a list of genes and siRNA sequences. For an inhibitor of LINC01679, two short single-stranded siRNAs are described, viz, SEQ ID NO: 19 and 20. The human oral squamous cell carcinoma cell line, SCC-15, is treated with the siRNA and resulting gene expression is determined. LINC01679 is knocked down significantly. Proliferation of the cells by a CCK8 assay, and migration by transwell assay are then determined and found to be significantly reduced as compared to control cells. Results are depicted in Tables 4 – 6.
Thus, Applicant provides written description for an interference RNA, which is a siRNA that comprises a sequence that is complementary to lncRNA sequence (lincRNA01679) represented by SEQ ID NOs: 19-20. Thus, an “RNA interference inhibitor of LINC01679” is provided.
Regarding the end-goal: The specification discloses treatment in vitro with the two disclosed siRNA inhibitors results in decrease in proliferation and migration of the treated cells.
The crux of the rejection is the end-goal: The specification provides no information on in vivo treatment, only treatment of cells are disclosed.
It is highly unpredictable that any interference RNA that is specific for LINC01679 (or any given target) will achieve the end-goal as recited.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of delivering an antisense oligomer and the resultant in vivo effects.
Method of treating ( in vivo); i.e., In vitro – In vivo correlation
The practice of a method without the need for substantial undue experimentation and additional inventive contribution requires the disclosure of an effective route, duration and quantity of administration of that inhibitor to a subject and this information is not provided by the instant specification. The background text on pages 1-2 of the instant specification clearly fails to supply the guidance that would be needed by a routine practitioner. In fact, this paragraph says, see quotation:
An in-depth understanding of the occurrence, development, invasion, and metastasis mechanism of OSCC, revealing the pro-oncogene and anti-oncogene of OSCC is conducive to improving and supplementing the treatment of oral squamous cell carcinoma, which has important clinical significance.
The instantly closed disclosure shows results of decrease in LINC01679 (discussed in written description section). However, this decrease has not been corelated with carcinoma in a subject. Therefore, one would not be able to reconcile the decrease seen by following instant method and achieving any treatment in a subject.
Absent Working Examples and Undue Experimentation
The instant specification has also failed to disclose how the parameter measured in vitro with the SEQ ID Nos recited in claims 29 and 35 may be translated to determine if treatment has been achieved in vivo, how a similar method was practiced in the art with a different agent or to provide even a single working example, prophetic or actual, of the claimed method. In the absence of this guidance a practitioner would have to resort to a substantial amount of undue experimentation involving the variation in the amount and duration of administration of a LINC01679 inhibitor of the instant invention and in determining a suitable route of administration.
The prior art provides no compensatory guidance for treating oral squamous cell cancer or inhibiting proliferation or migration of oral squamous cancer cells by inhibiting levels of a lncRNA in vivo. Without further guidance, in the spec. or the art, in an unpredictable field, one of skill in the art would have to empirically practice the instantly claimed invention.
State of the Art and Unpredictability in the Art
Oral squamous cell carcinoma (OSCC)
Tan (International Journal of Oral Science ( 2023) 15:44) review mechanisms involved in OSCC. With respect to genetic alterations drive the occurrence of OSCC, TP53/RB, p16/Cyclin D1/Rb, EGFR, Wnt/β-catenin, JAK/STAT, NOTCH, PI3K/AKT/mTOR, MET, RAS/RAF/MASK signaling pathways contribute to OSCC progression, have been well-documented (Fig. 2). In addition, OSCC exhibits epigenetic changes (Table 2) and phenotypic (EMT) plasticity (pg. 7, 2nd to the last para). With this background, it is highly unpredictable that one cell-line such as SCC-15 used by Applicants would recapitulate all the genetic, epigenetic, and EMT changes seen in OSCC.
zinc finger nucleases (ZFNs)
With respect to the zinc finger nucleases are programmed to target the LINC01679 locus, the art of Miller (Nature Biotechnology | VOL 37 | AUGUST 2019 | 945–952 |) evidences ZFNs specific for the TRAC locus that mediated 98% knockout in T cells with no detectable off-target activity at an assay background of ~0.01% (abstract). However, Miller cast doubt on the same efficiency in vivo. See recitation from 1st para:
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In vitro vs. In vivo methods
As stated above, while Applicant’s claim specifically encompasses in vivo embodiments “in a subject,” Applicant only provides working examples in vitro.
Regarding translation of in vitro methods to in vivo methods, Applicant is directed to:
1. the post-filing art of Mattes (Mattes, Current Opinion in Toxicology, Oct-Dec 2020, 23-24:114–118). Mattes evidences that around the time of filing, and post-filing, translating in vitro data to in vivo data is unpredictable. Specifically, Mattes evidences “the challenge of validating a system’s performance and extrapolating it’s responses to those of an animal or human remains” (abstract) and “the question of relevance to the in vivo setting remains an issue” (Summary; pg. 116).
2. The art of Arun (Trends Mol Med. 2018 Feb 12;24(3):257–277). Arun evidences that around the time of filing, treating in vivo with siRNA to lncRNA targets is unpredictable. Specifically, Arun evidences “Several lncRNAs have been knocked down using traditional siRNAs in cell lines [115,116]. However, in vivo experiments using siRNAs have been quite challenging. This is in part due to the lack of efficient delivery methods and limited bioavailability of siRNAs in animals [117,118].” (pg. 10, 2nd para).
Accordingly, because translation of in vitro methods to in vivo methods is unpredictable, Applicant cannot be enabled for instant claims, which encompass in vivo methods.
As the arts of Tan, Miller, Mattes and Arun, and the lack of evidence of the instant specification demonstrate, the obstacles that hinder the use of the claimed method in in vivo embodiments are not easy tasks to be done or solely routine experimentation to enable the claimed method. The type of experimentation would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” The degree of unpredictability has been discussed above. In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the method of the instant claimed invention.
MPEP
MPEP §2164.01(a), 4th paragraph, provides that, “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 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
MPEP 2164.02, pertains to the enablement requirement and section II is specific for CORRELATION: IN VITRO/IN VIVO . To describe this section succinctly, If there is no correlation, then the examples do not constitute "working examples." In instant case, Applicants have not shown data by use of an art-recognized model of oral squamous cell cancer that results seen in the SCC-15 cell line as utilized in instant assays can be reasonably extrapolated to a situation of oral squamous cell cancer. This is especially important in an unpredictable field such as the biological arts.
Conclusion
After applying the Wands factors and analysis to claims 25-26, 29-31, and 34-37, in view of the applicant’s entire disclosure, and considering the re Wright and re Genentech decisions discussed above, it is concluded that the practice of the invention as claimed in claims 25-26, 29-31, and 34-37 would not be enabled by the written disclosure excluding that of treating cells in vitro. Thus, the disclosure 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 (see MPEP 2164.01(a)). Accordingly, claims 25-26, 29-31, and 34-37 are rejected for lack of scope of enablement.
Examiner Suggestion: Applicants may consider using the phrase “for inhibiting LINC01679 target gene expression in a population of cells” as a claim limitation.
Response to Arguments
Applicant’s arguments, see Pgs. 10 - 12, filed 21st May 2026, with respect to Scope of Enablement rejections under 35 USC § 112(a) have been fully considered but are not persuasive. Applicants argue:
A The In Vitro Data Provides a "Specific, Substantial, and Credible" Utility.
The specification shows that with interfering RNA targeting LINC01679, the "abnormal proliferation" and "migration" of cancer cells is inhibited thus showing a Direct Correlation to Pathological Mechanism.
Patent law does not require the Applicant to have completed clinical trials or definitive in vivo animal studies at the time of filing.
The "Substantiality" requirement is met because the invention provides a concrete method for interfering with the disease mechanism.
Response: Applicants base their argument on §2107.01 General Principles Governing Utility Rejections, which requires "Specific, Substantial, and Credible" Utility to comply with §101 requirement. The issue in question is governed under §2164 The Enablement Requirement, which has a higher bar than the §101 requirement.
"abnormal proliferation" and "migration" of cancer cells is a phenotype and not a pathological mechanism.
A clinical trial or even robust In vivo studies are not required. However, there doesn’t seem to be a link between in vitro treatment in one cell line with the sequences recited and treatment of the condition that the cell line is meant to represent in a human, or even more broadly, in vivo.
A “concrete method for interfering with the disease mechanism” would require an art-accepted model of the disease. Applicants have not provided any data in this regard.
B. The "Separation" of Drug Activity from Drug Delivery.
Examiner's concern regarding the "unpredictable" of in vivo efficacy stems from a conflation of "Drug Activity" with "Drug Delivery." Availability of Routine Methodologies: It is well within the purview of the skilled artisan that interfering RNA can be delivered
The specification's obligation is to prove that "the interfering RNA (SEQ ID NO: 19-20) specifically inhibits LINC01679 and impairs cancer cell function." This obligation has been fulfilled by the in vitro experiments.
Response: 1. Applicants base their argument on a hypothetical argument of conflating "Drug Activity" with "Drug Delivery". Indeed drug delivery mechanisms are available. So are inhibitory RNA designs to a gene whose sequence is known. The question is, given all this knowledge in the art available to the skilled artisan, would one predictably i) inhibit the gene to ii) result in the phenotypic/ treatment changes one wishes to see. Applicants have not provided any argument or reference in this regard.
2. Applicants demonstrate a particular cancer cell line when treated with interfering RNA substantially decreases growth and migration of the cancer cell lines. However, the scope of claims extends beyond in vitro treatment of a particular cell line. Applicants evidence is not commensurate with the scope of claims. The evidence as a whole, i.e., all Wands factors discussed above, do not indicate that the results seen in vitro in one cell line would be seen in vivo.
C. "unpredictable" is a Research Risk, not a Legal Bar
Reasonable Expectation vs. Absolute Guarantee: Patent law requires a "reasonable expectation of success," not an "absolute guarantee of success." By providing rigorous in vitro data validating LINC01679 as a novel and effective therapeutic target, the application provides a solid foundation for the industrial utility of the invention.
Response: 2143.02 requires a reasonable expectation of success when referring to the likelihood of success in combining or modifying prior art disclosures. The section at issue here is §2164 The Enablement Requirement, which is distinct from the §103 Obviousness requirement.
D. Fulfillment of the Quid Pro Quo
Applicants argue, their disclosure of the specific interfering RNA sequences, the target information, and concrete in vitro activity data implies the corresponding patent protection. Rejecting the application based on potential future clinical translational failures would be tantamount to punishing fundamental early research.
Response: The patent protection sought must be commensurate with claims. Applicants claims are broader than what is enabled by the disclosure. Applicants arguments are not dispositive. The scope of enablement rejection is maintained.
Withdrawn Claim Rejections - 35 USC § 103
Applicants have overcome the rejection by providing an English language translation of the foreign application and establishing the priority date.
Conclusion
No claims are 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/CATHERINE KONOPKA/ Primary Examiner, Art Unit 1635
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