DETAILED ACTION
The Examiner of record has changed.
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 .
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 is acknowledged.
Additionally, Applicant’s election without traverse of the following Species:
I. LINC01679;
in the same reply is acknowledged.
Claims 14-24 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim.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.
Accordingly, claims 25-33 are under examination.
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 no English language translation has been provided.
Specification
Trade name
The use of the term “Nanodrop”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Abstract
The abstract of the disclosure is objected to because:
The abstract is replete with errors.
For e.g., the last line of the abstract states: the biomarkers are also used in the preparation of a pharmaceutical composition for treating oral squamous cell carcinoma and a pharmaceutical composition for treating oral squamous cell carcinoma.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 25 – 28 and 30 - 33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim Interpretation
The following are recitations from independent claims 25 and 30:
claim 25
claim 30
A method
A method
for preventing or treating oral squamous cell carcinoma
for preventing or treating oral squamous cell carcinoma
the method comprises:
the method comprises:
administering to a subject a pharmaceutically effective amount of
administering to a subject a pharmaceutical composition comprising
an inhibitor of LINC01679
an inhibitor of functional expression of LINC01679
As per pg. 10 of the specification, "functional expression" of lncRNA, can be deregulated at least at two levels. First, at the DNA level, for example, by deletion or disruption of the gene, or no transcription occurs; .. Second, at the RNA level, e.g., by lack of efficient translation-e.g., because of instability of mRNA ( e.g., by UTR variants), may result in degradation of mRNA prior to translation of the transcript. Or by lack of efficient transcription. The specification on pg. 11 continues to state: suppression of functional expression of a gene, can also be achieved, for example, by … antisense RNA. There is no definition for inhibitor.
Thus, the specification makes no distinction between an inhibitor and inhibitor of functional expression as recited in claims 25 and 30 respectively. Further, the descriptions provided above are not limiting definitions, and so inhibitors could encompass: direct or indirect inhibition, with compounds possessing the activity or effect specified in the claims. Such compounds could be small molecules, nucleic acid inhibitors, polypeptides, etc. Interference oligomers are described as: siRNA or gapmers (instant specification pg. 13-14), which again are not limiting definitions.
Therefore, both claims are being given the broadest reasonable interpretation which is: a method to treat/prevent oral squamous cell carcinoma with an inhibitor of LINC01679.
Applicants disclose in pg. 6: the subject is a human.
Scope of the Invention
The rejection is limited to the elected invention (claims 25-26: method for preventing or treating oral squamous cell carcinoma with an inhibitor of LINC01679; and dependent claims 27 – 28; claims 30-33: method for preventing or treating oral squamous cell carcinoma with an inhibitor of expression of LINC01679).
Disclosure of a Complete or Partial structure
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 “inhibitor of the biomarker” and “inhibitor of functional expression of the biomarker" is provided.
Regarding the end-goal: The specification discloses treatment in vitro with the two disclosed inhibitors results in decrease in proliferation and migration of the treated cells.
Species not Disclosed
On pgs. 10-14, Applicants disclose: knock-out, CRISPR RNA, aptamers and ribozymes, as possible inhibitors.
However, this background information does not provide written support for the types of functional inhibitors as required by the claims.
Although the specification discloses 2 exemplary siRNAs that are specific for inhibiting "functional expression" of linc01679, the specification does not describe any other inhibitors.
Given the breadth of inhibitors embraced in the instantly claimed genus, one could not envision the member agents that are encompassed such a broad genus.
Regarding the end-goal: The specification provides no information on in vivo treatment or prevention, only treatment of cells are disclosed. Further, the scope of the claimed invention is broad and the skilled artisan would not be able to envisage the entire genus claimed of inhibitors that inhibit the "functional expression" of the lncRNA, LINC01679.
Structure/Function Correlation
Antisense oligonucleotides, siRNA and shRNA have a different structure and/or mechanism of action compared to other types of inhibitors or even other nucleic acid molecules encompassed by interference RNA. There is no essential structure of record required for inhibitors or inhibitor of functional expression or interference RNA inhibitor to treat oral squamous cell carcinoma in a subject that would support written description for the genus of inhibitors.
The skilled artisan cannot envision small molecules, peptides, aptamers and ribozymes having the desired biological activity (treat oral squamous cell carcinoma by reducing LINC01679 expression) based on the nucleic acid inhibitors described in the specification. Other than generically contemplating these molecules, the specification does not provide adequate written description of the small molecules, peptides, aptamer, ribozyme itself. See MPEP 2163, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). While it is acknowledged that it is routine and conventional to prepare these molecules, in view of MPEP 2163, adequate written description of LINC01679 inhibitors requires more than just generically contemplating the species of inhibitors.
With respect to the inhibitor is a CRISPR, TALEN, or zinc finger nuclease, as recited in claims 27 and 32, the skilled artisan knows how to design such RNAi agents. However, in instant case, the skilled artisan doesn't know what gene/protein to target them against in the case of an indirect inhibitor.
In view of the lack of description for these species, the skilled artisan would have to empirically determine if a given molecule has the desired biological activity.
Method of Treatment / Prevention
To demonstrate possession of a method of treatment or prevention one must provide substantially more than the description of a compound having in vitro activity, in combination with a hypothesis that the administration of a compound having that activity to an individual suffering from a particular disease or disorder might produce a beneficial effect. What is required is an established nexus between the administration of such a compound to an individual and a beneficial result consequent thereto. Such a nexus can be established by the presentation of evidence demonstrating clinical efficacy of the claimed method in the treatment or prevention of a particular disease or disorder, demonstrating efficacy of that method in the treatment or prevention of an art accepted animal model of a disease or disorder wherein that model is known to be reasonably predictive of the efficacy of a treatment or prevention protocol in the treatment of that disease or disorder, or providing evidence of an in vitro activity for the recited compound in combination with a showing that other compounds possessing that activity (mode of action) have been shown to have clinical efficacy in the treatment or prevention of the recited disease or disorder. The instant specification fails to show possession of the claimed method as of the effective filing date of the instant application because it provides none of these.
MPEP
As stated in MPEP 2163(II)(A)(3), a specification may describe an actual reduction to practice by showing that the inventor constructed an embodiment or performed a process that met all the limitations of the claim and determined that the invention would work for its intended purpose. Cooper v. Goldfarb, 154 F.3d 1321, 1327, 47 USPQ2d 1896, 1901 (Fed. Cir. 1998). See also UMC Elecs. Co. v. United States, 816 F.2d 647, 652, 2 USPQ2d 1465, 1468 (Fed. Cir. 1987) (“[T]here cannot be a reduction to practice of the invention ... without a physical embodiment which includes all limitations of the claim.”); Estee Lauder Inc. v. L’Oreal, S.A., 129 F.3d 588, 593, 44 USPQ2d 1610, 1614 (Fed. Cir. 1997) (“[A] reduction to practice does not occur until the inventor has determined that the invention will work for its intended purpose.”); Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1578, 38 USPQ2d 1288, 1291 (Fed. Cir. 1996) (determining that the invention will work for its intended purpose may require testing depending on the character of the invention and the problem it solves).
Whereas a reduction to practice of an uncomplicated invention such as a simple mechanical or electrical device can be achieved by merely providing a diagram of the device wherein one skilled in the relevant art can predict the likely operability of the device by reviewing the diagram, the operability of the claimed invention cannot be predicted by merely reviewing diagrams or illustrations. To demonstrate the reduction to practice of a method of treating or preventing a recurrence of an infection or disease in an animal requires either a working embodiment, a demonstration of operability in the prevention method, an art accepted animal model of the condition to be prevented wherein that animal model has been shown to be reliably predictive of efficacy in the prevention of the condition, or a demonstration that the treatment or preventive agent employed therein possesses an activity in which the majority of compounds possessing that activity have been shown to be effective in the prevention of that condition.
The instant specification, however, fails to describe even a single example of the successful reduction to practice of a method of treating or preventing oral squamous cell carcinoma by the administration of a LINC01679 inhibitor to a mammal afflicted therewith. In fact, the specification fails to provide evidence that LINC01679 inhibitors in general are treatment or preventive options (in vivo) or that a representative number of species of such compounds have ever been shown to produce a beneficial treatment or preventive response when exogenously administered to a mammal afflicted with oral squamous cell carcinoma. Further, whereas the clinical administration of ASO inhibitors to subjects afflicted with a disease was a practice that was old and well known in the art before the filing of the instant application, there is no evidence that in vivo treatment or preventive activity has ever been reported for LINC01679 inhibitors, and Applicant provides no evidence to the contrary.
An adequate written description of such a method of preventing requires the disclosure of specific protocol that has been shown or can reasonably be predicted to produce the desired result.
In addition, the prior art and the as-filed specification do not provide written description for any molecule that indirectly inhibits LINC01679 expression in a cell representative of oral squamous cell carcinoma, in vitro or in vivo.
Conclusion
The written description requirement for the claimed genus of inhibitors is not satisfied through sufficient description of a representative number of species. There is substantial variation within the genus of agents that are LINC01679 inhibitors, and the applicant does not described a sufficient variety of species to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163.
In view of the foregoing, it is clear that the instant specification fails to convey that the inventors had possession of the genus of LINC01679 inhibitors in claims 25 and 30, and/or methods of inhibiting LINC01679 expression to effectuate prevention and/or treatment in a subject, as of the effective filing date sought in the instant case. Only methods of treating cells by decreasing expression of LINC01679 comprising siRNA that have substantial complementarity to select target regions within LINC01679 gene disclosed by SEQ ID NO: 19 and 20, and not the full breadth of the claims, is supported by Applicant’s disclosure.
Dependent claims 26-28 and 31-33 are also rejected because they depend on Claim 25 and 30 respectively and do not remedy the issues of lack of written description as discussed above. For instance, claims 27-28 and 32 are broad recitations of inhibitors and not followed by recitations that limit for e.g., the targets for indirect inhibition. For a gene such as LINC01679, for which sufficient knowledge regarding pathways of which it may be a part of are not known, a specific target to which inhibitors could be designed is consequently not known. Therefore, with no information on a target, designing an inhibitor is empiric.
SEQ ID Nos are recited in claim 29 and these sequences have support in the disclosure. Therefore, claim 29 is not included in the rejection.
Examiner Suggestion: Amend the independent claims to recite limitations for which there is adequate written description support in the disclosure or prior art. For e.g., amend:
the structure of an inhibitor or recite publicly available or deposited clones expressing the same; for e.g., limit the inhibitor to an RNA interference inhibitor that comprises a sequence that is complementary to the LINCO1679 transcript and limit the nuclease to those programmed to target the LINCO1679 locus.
The instant broad recitation to: an in vitro method such as decreasing LINC01679 in cancer cells.
Claims 25 –33 are 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 in cells comprising administering an siRNA specific for LINC01679, does not reasonably provide enablement for the instant method of treating or preventing oral squamous cell carcinoma in vivo and also does not provide enablement for inhibiting LINC01679 expression with any inhibitor. 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.
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.
The Nature of the Invention
The invention is drawn to a method of preventing or treating oral squamous cell carcinoma in a subject in need thereof.
Breadth of the Claims
Instant claims encompass:
“treating” and “preventing”
This encompasses both treatment of an existing disease or prevention of a disease, i.e. prophylaxis. Prophylactic can be understood as preventing a normal or preneoplastic cell from turning into a carcinoma. The specification provides no definition/description of the term.
“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.
These encompass all possible agents that are capable of decreasing levels of LINC01679 mRNA which includes: All possible proteins or RNA/DNA that encodes them that are present at any point in a biological pathway of LINC01679 mRNA or protein that would affect the pathway and result in an decrease of LINC01679 mRNA;
All possible inhibitors of all possible types (i.e. RNA interference agents, pharmaceutical inhibitors, prions and others) of proteins or RNA/DNA that encodes them that are present at any point in a biological pathway of LINC01679 mRNA or protein that would affect the pathway and result in an decrease of LINC01679 mRNA;
All possible pharmaceutical agents that decrease LINC01679 mRNA or protein by acting directly on LINC01679 mRNA or protein or any point in a biological pathway of LINC01679 mRNA or protein that would affect the pathway 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.
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 25-28 and 30-33), but rather refer to the broad genus of inhibitors of LINC01679 genes including all (possible) variants.
The instant claims embrace contacting any biological system via any means of delivery with any antisense oligomer so that LINC01679 levels are decreased.
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 with minimal specificity to a target sequence and the resultant in vivo effects.
Method of treating or preventing ( in vivo); i.e., In vitro – In vivo correlation
As discussed for the written description section above, there is no disclosure on how treatment or prevention is achieved. Only in vitro treatment of a cell line is described.
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 or prevention 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 claim 29 may be translated to determine prevention or 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.
Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
State of the Art and Unpredictability of the Art
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 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).
Regarding translation of in vitro methods to in vivo methods, Applicant is directed to 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.
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.
Conclusion
After applying the Wands factors and analysis to claims 25-33, 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 25-33 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 –- 33 are rejected for lack of scope of enablement.
Examiner Suggestion: Since claims are enabled only for inhibiting LINC01679 target gene expression in cells comprising administering the siRNAs: SEQ ID NO: 19 and 20, the suggestion made in the written description section applies here as well.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
This rejection may be overcome by providing an English language translation of the foreign application and establishing the priority date.
Claims 25 – 28 and 30 - 33 are rejected under 35 U.S.C. 103 as being unpatentable over Han (CN 112063706 A), as evidenced by the machine translation into English, in view of Wu (CN110387372 A), as evidenced by the machine translation into English.
Regarding claims 25 and 30, Han teaches a method of treating cells, the method comprising treating the cells with siRNA directed to the target biomarker gene LINC01679 (title, abstract). Han teach that pterygium represents epithelial overgrowth / hyperplasia /tumor-like characteristics (background 2nd para, [0004]). Han first teaches establishing LINC01679 as a biomarker in such pterygium tissue wherein increased expression in pterygium compared to normal conjunctiva cells is seen (Embodiment 1). Next, Han teaches culturing primary cells from human primary pterygium (hPEC) [0024] and treating the same with an inhibitor to LINC01679 (siRNA, Embodiment 3). Han provide the sequences of target specific siRNAs. Han observe that following treatment, the proliferation, migration, and invasiveness of hPECs decrease compared to untreated hPECs ([0045], Embodiment 3; Figs. 3-5). Han contemplate the use of the siRNAs in the preparation of drugs for treating various tumors ([0007] and [0012]).
Regarding claims 26 and 31, the method of claims 25 and 30 is discussed above. Han further teaches that on application of the method, a decrease in expression of LINC01679 occurs by decreasing expression of RNA transcripts of LINC01679 (Fig. 4B).
Regarding claims 27 and 32, the method of claims 25 and 30 is discussed above. Han further teaches that the inhibitor used in the method of decreasing expression of LINC01679 is an interference RNA (claim 6).
Han do not teach a pharmaceutically effective amount or a pharmaceutical composition comprising the described inhibitor and pharmaceutically acceptable carrier (claims 25, 30, and 33).
However, before the effective filing date of instant invention, Wu had taught many lncRNAs are aberrantly expressed in cancers, may be of etiological importance, and inhibiting the aberrantly expressed lncRNAs may be therapeutic. See relevant recitations from Wu:
[0005]: lncRNAs can participate in the development and progression of tumors as oncogenic or tumor suppressor genes. By comparing the expression profiles of tumor cells and normal cells, it was found that multiple lncRNAs are abnormally expressed in different types of tumors. lncRNAs hold promise as novel tumor markers and targets for tumor therapy, enabling their use in tumor diagnosis, treatment, and prognostic monitoring.
[0007] Recent studies have found that aberrant expression of lncRNAs plays an important role in the malignant development of tumors, participating in angiogenesis, cell proliferation, migration, and apoptosis.
Claim 6.Use of an inhibitor that inhibits the expression of 00211901 lncRNA as set forth in SEQ ID No: 1 in the manufacture of a medicament for the treatment of gastric cancer.
Towards this goal of treating cancer, Wu provided the siRNA inhibitor to a particular lncRNA that is aberrantly expressed in gastric cancer in a pharmaceutical composition and a pharmaceutically acceptable carrier (Wu claims 4-5 and 7).
Therefore, the method taught by Wu presents a viable option for packaging an inhibitor to a lncRNA, which is an siRNA, in a pharmaceutical composition so as to use the same in a method of treating cancer.
It would have been prima facie obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to have combined an siRNA as an inhibitor to LINC01679 as taught by Han with a pharmaceutically acceptable carrier to make a pharmaceutical composition, as taught by Wu, for the advantage of using it in a treatment method for oral squamous cell carcinoma. One of ordinary skill in the art would have been motivated by Han’s teachings that LINC01679 is a target gene because its upregulation indicates it to be a biomarker of hyperplasia and oral squamous cell carcinoma, which like pterygium, is also of epithelial origin. One of skill in the art would have a reasonable expectation of success in combining the teachings because both Han and Wu teach siRNA as an inhibitor to a lncRNA as a treatment option. See MPEP 2143 I. Exemplary Rationale (A) and MPEP 2144 II.
Thus, Han in view of Wu makes obvious instant claims 25 – 28 and 30 - 33.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Han (CN 112063706 A), as evidenced by the machine translation into English, in view of Wu (CN110387372 A), as evidenced by the machine translation into English, as applied to claims 25 – 28 and 30 - 33 above and further in view of Arun (Arun, Trends Mol Med. 2018 Feb 12;24(3):257–277) and Fakhr (Fakhr, E., Zare, F. & Teimoori-Toolabi, L. Cancer Gene Ther 23, 73–82 (2016).
Regarding claim 29, Han and Wu teach a method of treating cells, the method comprising treating the cells with siRNA directed to the target biomarker gene LINC01679.
Neither Han nor Wu teach the specific nucleotide sequences of the 21-mer disclosed in instant application that target LINC01679; i.e., SEQ ID NO: 19 or 20.
However, Han taught the Gene sequence of LINC01679 (Han, SEQ ID NO: 1) and Arun taught that knocking down a target with siRNAs was a mature field (RNAi, bridging pgs. 9-10). See specific recitation from pg. 10, 2nd para:
Several lncRNAs have been knocked down using traditional siRNAs in cell lines [115,116].
The reference cited by Arun (115) recites in their 2nd para: on transfection of synthetic 21-nucleotide siRNA … promote degradation of complementary RNA sequences. Arun taught lncRNAs as viable therapeutic targets with nucleic acid therapeutics (last line of abstract). Once potential sequences are identified, Arun teaches that bioinformatics analyses helps to eliminate sequences with potential off-target matches (pg. 14, first para).
Neither Han nor Arun provide any further guidance other than 21 nucleotide complementarity for siRNAs.
However, Fakhr teaches applying known cellular pathways of RNA interference for efficient siRNA design using automated tools, software, and algorithms (abstract and Fig 1). Fakhr teaches -efficiency of siRNA molecule design depends on known factors including target availability, secondary structures of mRNA, position of matching and intrinsic characteristics of siRNA and mRNA (pg. 73 para 4). Fakhr teaches detailed basic criteria for designing efficient siRNA for gene expression inhibition which includes target site factors, length of siRNA, specificity checking, and nucleotide content (pg. 73 para 5 and Table 1). Fakhr teaches efficient siRNA length of 19 as well as longer siRNAs ranging from 21 to 29 nucleotides with very good results (pg. 74 para 1). Fakhr teaches asymmetrical nucleotide content in the duplex for increasing targeting, with more G/C content at the 5′-end of the sense strand and more A/U at the 3′-end (pg. 75 para 4). Fakhr teaches other available known and effective siRNA design programs including AsiDesigner, siDesign and RNAi codex, Oligowalk (Table 2 pg. 77). Fakhr further teaches a scoring system for enhanced siRNA design to optimize gene targeting (pg. 79, Fig 3).
It would have been obvious to one of ordinary skill, before the effective filing date of instant application, to try to make siRNA sequences sufficiently similar to Applicant’s SEQ ID NO: 19 and 20 using the siRNA design system of Fakhr and guidance from Arun along with the sequence taught by Han in order to target LINC01679. Before the effective filing date of Applicant’s invention, Fakhr taught a design need for nucleic acid sequences which can influence target gene expression in multiple species. SiRNA targeting systems rely on a finite number of identified parameters such as target length, limited RNA nucleotides, combinations of nucleotides, and nucleotide length less than 30nt but ideally between 19 and 25nt, with a finite number of identified, predictable sequences. The length of human LINC01679 mRNA taught by Han is ~2906 nucleotides long and to make siRNA of 21 nucleotides would mean . Thus, there are ~2885 possible 21-mers that can target known RNA with 100% identity. As such, there are finite number of identified solutions evidenced by the sequence of LINC01679. The large, but finite number of possible solutions becomes much smaller and their function even more predictable once the skilled artisan makes use of the known screening tools taught in Fakhr. It would have been obvious to try siRNA sequences from the sequence of LINC01679 because Fakhr demonstrates that given a known target, antisense sequences can be generated within their design system to influence gene expression with a measured and predictable outcome and because Arun taught that off-target matches could be eliminated by bioinformatic screening, further establishing the need to “try” the sequences to find optimal candidates. The skilled artisan would have had a reasonable expectation of success using Fakhr’s siRNA design system to make siRNA targets for SEQ ID NO: 14 of the LINC01679 gene because Fakhr teach detailed parameters of successful gene targeting such as ~21 nucleotide length and asymmetrical nucleotide content in the duplex with more G/C content at the 5′-end of the sense strand and more A/U at the 3′-end. Thus, Fakhr’s siRNA design system to generate sufficiently similar siRNA sequence to SEQ ID NO: 19 and 20 from a known target would yield siRNA which predictably inhibits the LINC01679 gene. See MPEP 2143 I (E).
Thus, Han and Wu in view of Arun and Fakhr make obvious instant claim 29.
Therefore the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains.
Conclusion
No claims are allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
SHABANA S. MEYERING, Ph.D.
Examiner
Art Unit 1635
/SHABANA S MEYERING/ Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635