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 .
Applicant's election with traverse of group I and the species TROLL-2, breast cancer, TAP63 regulated, and siRNA in the reply filed on 10/1/25 is acknowledged. The traversal is on the ground(s) that the office action has not shown that there is a serious burden. This is not found persuasive because search burden is not a consideration in 371 applications. Additionally, the present of six different TROLL gene/transcripts, each having a different sequence and activities does in fact present a serious search burden. siRNAs targeting each of the TROLL transcripts have different sequences and activities.
The requirement is still deemed proper and is therefore made FINAL.
Claims 10, 14, 16, 18, 20, 23, and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 10/1/25.
Drawings
The drawings filed on 5/20/26 are objected to because color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Improper Markush Rejection
Claims 1, 2, 5, 8, 12, 21, and 22 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims are directed to a method of knocking down six different lncRNAs, each being over a thousand nucleotides in length and having different isoforms. The sequence and activity of each is different, wherein the activity is dependent upon the specific sequence of nucleotides. Although the claims have been amended to require two or more of the lncRNAs to be knocked down, the claims are not limited to two and applicant has previously elected one.
Additionally, the claims are directed to delivery of antisense oligonucleotides, siRNA, shRNA, ribozymes, TALEN, AFNs, or CRISPR/Cas nucleases, each of which has a different structure and acts via a different mechanism. One cannot be substituted for another with expectation of identical activity.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled:
(A) All alternatives have a common property or activity; and
(B) (1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or
(B) (2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together.
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific type of RNA-targeted therapeutic is dependent upon the specific structure. There is no expectation that any one of the therapeutics as claimed can be substituted for any of the other with a different structure that acts via a different mechanism with the expectation of the same activity; and there is no expectation that knocking down the expression of any one target would result in the same outcome as knocking down a different target with a different sequence. Additionally, agents targeting each of the targets each have different structures and/or sequences, resulting in different activities.
As set forth in MPEP2117, “Note that where a Markush group includes only materials from a recognized scientific class of equivalent materials or from an art-recognized class, "the mere existence of such a group in an application tend[s] to prove the equivalence of its members and when one of them [is] anticipated the group [is] therefore rendered unpatentable, in the absence of some convincing evidence of some degree of non-equivalency of one or more of the remaining members." In re Ruff, 256 F.2d 590, 598-99, 118 USPQ 340, 348 (CCPA 1958)("[A]ctual equivalence is not enough to justify refusal of a patent on one member of a group when another member is in the prior art. The equivalence must be disclosed in the prior art or be obvious within the terms of Section 103." Id. at 599, 118 USPQ at 348).”
In the instant case, art against any one therapeutic or target sequence would not be evidence against any of the remaining members that have completely different structures and/or sequences and do not have identical activity.
Response to Arguments
Applicant respectfully refers the Examiner to working Example 1 of the present application entitled "Pan-Cancer Analysis Reveals TAp63-Regulated Oncogenic lncRNAs (TROLLs) that Promote Cancer Progression Through AKT Activation." Therein, an inducible CRISPR/Cas9 system of TAp63 knockdown led to an associated upregulation of 6 IncRNAs and downregulation of 3 IncRNAs (i.e., 9 human Tap63-regulated oncogenic IncRNAs, "TROLL" IncRNAs), whereas overexpression of TAp63 in the same cells led to the opposite effects in these 9 human IncRNAs (see, e.g., FIGs. 1D, 2D-2G of Example 1). Having established this direct relationship between TAp63 and the 9 TROLL IncRNAs, Applicant subsequently found TAp63 binding sites in the promoters of all 9 TROLL lncRNAs (see, e.g., FIG. 2H of Example 1). Moreover, chromatin immunoprecitipation (ChIP) revealed TAp63 recruitment to these sites (see, e.g., FIG. 21 of Example 1). In summary, these TROLL IncRNAs share a common property or activity, e.g., TAp63-regulated expression and role in promoting cancer progression, that naturally flows from having the same significant structural element (the TAp63 binding site in their promoter).
Although applicant has identified that Tap63 binding sites are present in the promoters of the 9 TROLL lncRNAs, the instant claims are directed to a method of administering any RNA-targeting therapeutics that knock down the expression of six different lncRNAs, each being over a thousand nucleotides in length and having different isoforms. The claims do not require targeting of any common sequence between the lncRNAs, but rather encompass delivering completely different types of therapeutics that have different structures and act via different mechanisms that target completely different target nucleotide sequences.
Applicant argues that the Examiner also alleges that the claims are directed to delivery of antisense oligonucleotides, siRNA, shRNA, ribozymes, TALEN, AFNs, or CRISPR/Cas nucleases and each of these has a different structure and acts via a different mechanism. Applicant respectfully disagrees because each of these chemical compounds are all "RNA-targeted therapeutics," in other words, chemical compounds which have the capability of targeting and knocking down expression of RNA molecules, such as the TROLL IncRNAs of the currently amended claims. Being an RNA-targeted therapeutic is not a substantial structural similarity. This language is very broad and encompasses an enormous genus of possible agents that each have a different structure and act via different mechanisms.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific type of RNA-targeted therapeutic is dependent upon the specific structure. There is no expectation that any one of the therapeutics as claimed can be substituted for any of the other with a different structure that acts via a different mechanism with the expectation of the same activity; and there is no expectation that knocking down the expression of any one target would result in the same outcome as knocking down a different target with a different sequence. Additionally, agents targeting each of the targets each have different structures and/or sequences, resulting in different activities.
It is noted that claim 12 was not previously rejected because it limited the scope to specific siRNAs targeting the elected lncRNA. However, since claim 1 now requires knockdown of two or more of the lncRNAs, claim 12 does not limit the second RNA-targeted therapeutic.
It is noted that as currently drafted, claim 1 link(s) the therapeutics of claim 8. The restriction requirement among the linked inventions is subject to the nonallowance of the linking claim(s), claim 1. Upon the allowance of the linking claim(s), the restriction requirement as to the linked inventions shall be withdrawn and any claim(s) depending from or otherwise including all the limitations of the allowable linking claim(s) will be entitled to examination in the instant application. Applicant(s) are advised that if any such claim(s) depending from or including all the limitations of the allowable linking claim(s) is/are presented in a continuation or divisional application, the claims of the continuation or divisional application may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Where a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. In re Ziegler, 44 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
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 1, 2, 5, 8, 12, 21, and 22 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.
The claims recite a genus of lncRNAs, wherein TROLL-2 is the elected lncRNA. However, the specification does not adequately describe the structure required for the genus of “TROLL-2” sequences. Instant claim 11 previously recited a TROLL-2 isoform by Genbank Accession number, which is evidence that the term “TROLL-2” is not limited to any specific sequence. The specification does not disclose any other isoforms of TROLL-2 and does not specifically disclose the sequence of the isoform previously recited in claim 11. Without further description of the structure required, one would not be able to recognize which sequences are necessarily included or excluded from the terminology “TROLL-2”.
Without further description of the specific sequence in the specification, one would not be able to recognize that applicant was in possession of the entire claimed genus at the time of filing.
The claims do not recite a specific TROLL-2 nucleotide sequence by SEQ ID NO, but rather refer to the undefined genus of TROLL-2 sequences. The same is true for recitation of TROLL-1, 3, 5, 7, and 8. Without further description of the sequences, one would not be able to readily envision the member species.
The claims encompass knocking down the expression of TROLL-2 via any possible RNA therapeutic and therefore a method of introducing any type of TROLL-2 RNA targeting therapeutic to inhibit the expression of any TROLL-2 sequence, as well as encompass any TROLL-2 homolog or allele from any species known or yet to be discovered of TROLL-2, as well as DNA genomic fragments, spliced variants or fragment that retains TROLL-2 -like activity. The specification does not adequately describe this genus and does not disclose even a single species of TROLL-2 sequences by SEQ ID NO.
Although the specification discloses some inhibitory molecules such as antisense oligonucleotides, siRNA, shRNA, ribozymes, transcription activator-like effector nucleases (TALEN), zinc finger nucleases (ZFNs) and/or clustered regularly interspaced short palindromic repeats/associated (CRISPR/Cas) nucleases, disclosure of this broad genus is not an adequate description of the actual genus of compounds that would result in the function of knocking down the expression of TROLL-2 by being a RNA-targeting therapeutic. Claim 1 is not limited to these agents and even with regards to claim 8, which recites these agents, the agents are not required to have any specific structural relationship with any specific TROLL-2 sequence. Additionally, the agents can act on any target that has a secondary effect of knocking down TROLL-2, which is a genus of agents that has not been adequately described in the specification.
The specification does not describe any other RNA-targeting therapeutics directed to any other species of TROLL-2 to describe the instantly claimed genus of any TROLL-2. Each of the instantly disclosed agents are siRNAs specifically targeted to a single sequence, although the claims are drawn to any RNA-targeted therapeutic for knocking down any TROLL-2. One of ordinary skill in the art could not make such agents to any TROLL-2 without knowledge of the sequence and knowledge of the structure of the agent. Given the breadth of sequences embraced in the instantly claimed genus, one could not envision the member agents that target such a broad genus.
With regards to instant claim 5, the specification does not adequately describe the genus of breast cancers that are “Tap63 regulated”. Without further knowledge of the genus, one would not be able to readily envision which breast cancers are regulated in any manner by Tap63.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
With regards to the elected species, siRNA, it appears that the structure is required to have an antisense strand that is fully complementary to a target sequence in order to achieve the desired function. For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888). The instant siRNAs are not even required to have a strand that targets TROLL-2, but rather can target any target that has the secondary effect of knocking down TROLL-2.
The specification does not clearly define “RNA-targeting therapeutics”, but rather gives examples as set forth in instant claim 8. Even these examples are not required to have any specific structural relationship to any specific target sequence. For example, the claims encompass siRNAs that have a complementary strand to and are targeted to any possible target that has the effect of knocking down TROLL2. Additionally, small molecule inhibitors, peptides, ribonucleases, antibodies, aptamers, and riboswitches can be RNA-targeting therapeutics.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for instant genuses that have the required functions. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues that much in the same way as mRNA or proteins may have two or more different splicing isoforms, IncRNAs may have different transcript isoforms. Even if there are multiple different isoforms for a specific mRNA/protein/IncRNA, however, there are substantial teachings in the art for a person of skill to associate an individual mRNA/protein/IncRNA with its associated isoforms. The present application provides several examples to this effect, where different human isoform transcripts of an individual IncRNA (e.g., TROLL-3 having four isoforms, including published transcript sequences which are identified by Genbank Accession Nos. NR_034108.1, NR_034109.1, NR_034110.1, and NR_034111.1) are specifically enumerated throughout the specification. There would be no doubt to a person of skill in the art where and how to find these human sequences and how to target these in a human subject based on the application and the currently amended claims, for example by an siRNA comprising the nucleic acid sequences as currently claimed.
Contrary to applicant’s argument, although TROLL-2 is a single gene, it can have multiple isoforms that have not been adequately described in the specification. As instantly drafted, the claims are directed to any RNA-targeting therapeutic that knocks down the expression of any of these possible isoforms, which is a genus of sequences that have not been adequately described in the specification. One would not be able to readily envision any RNA targeted therapeutic that knocks down the expression of an undefined genus of sequences. The examples of the specification of “expression of TROLL-2 is knocked down by targeting the RPSAP52/NR_026825.2 isoform of TROLL-2” is not adequate description of the entire possible genus.
Although applicant argues that it is clear that the RPSAP52 IncRNA TROLL-2 was well-known in the art, this specific species was well known in the art. The question is what other sequences are encompassed in the instant claim language of “TROLL-2”.
Applicant argues that Applicant is not claiming the sequence of the IncRNA knockdown target. Rather, the currently amended claims provide for methods of using RNA-targeted therapeutics for knocking down expression of various human TROLL IncRNAs in a human subject, among these include the human TROLL-2, while providing specific sequences of RNA-targeting therapeutics in claims 10, 12, 14, 16, 18, 20, 23, and 24.
Although applicant is not claiming the lncRNA, knowledge of the specific target sequence is required in order to envision the RNA-targeting therapeutics of the method. The minimal species of examples of TROLL-2 siRNAs of the specification are not representative of the entire possible genus of target sequences or of all possible RNA-targeted therapeutics that would result in knockdown of any TROLL-2.
Applicant argues that knocking down expression of an RNA target by use of RNA-based therapeutics including, but not limited to antisense oligonucleotides, siRNA, shRNA, ribozymes, transcription activator like effector nucleases (TALEN), zinc finger nucleases (ZFNs) and/or clustered regularly interspaced short palindromic repeats/associated (CRISPR/Cas) nucleases, was a well-known and routine practice in the art at the time of filing the present application.
This is true when the target sequence is defined and the structure required for the RNA-based therapeutic in relation to the specific target is known. In the instant case, the structure required for the function of the RNA-based therapeutic has not been adequately described and the genus of possible target sequences have not been adeuqaly described. Without further description, one would not be able to readily recognize which RNA-targeting therapeutics with what specific structural relationship to what target sequence would result in knockdown of the recited target(s).
Applicant argues that in the example of TROLL-2, which as mentioned above has a single transcript associated with this IncRNA, all siRNA sequences were designed to this single transcript. It could not be confused, therefore, whether or not the siRNA sequences disclosed (SEQ ID NO: 13, SEQ ID NO: 14, and/or SEQ ID NO: 15) target TROLL-2.
It is agreed that all siRNAs of the specification are directed to a single target. The issue is that the claim language is not limited to any specific target sequence. The minimal species of TROLL-2 siRNAs of the specification are not representative of any RNA-targeting therapeutic that results in knockdown of TROLL-2.
Applicant argues that allegations of other possible unknown TROLL-2 sequences by the Examiner are purely speculative and inappropriate and that TROLL-2 is limited to a single sequence.
Contrary to applicant’s argument, Oliveira-Mateos et al. (Nature Communications, 2019, 10:3979, 1-18) teach that RPSAP52 has two isoforms in breast cancer cell lines, Genbank NR_026825.2 an and alternative transcript containing an additional 104-nucleotide internal exon (page 2).
Regarding claim 5, applicant argues that as unambiguously described in paragraph 67 on page 36 of the application as originally filed, it was "previously shown that loss of TAp63 leads to the onset of highly metastatic mammary adenocarcinomas to distant sites" such as lung, liver, and brain (see, e.g., paragraph 45 on page 21 of the application as originally filed). Specific TAp63-regulated breast cancers are disclosed in the present specification as originally filed, including but not limited to mammary adenocarcinoma and triple negative breast cancer (TNBC).
However, the species are not representative of the entire claimed genus. The claim is not limited to the cancers of the specification that have loss of Tap63, but rather are directed to any cancer that is regulated in any manner by Tap63.
With regards to Elbashir et al., applicant notes that each and every siRNA nucleotide sequence disclosed in the present application, SEQ ID NOs: 10-36, are exactly 19 nucleotides (nt) in length (see, e.g., Table 2 of the application as originally filed). Each of these sequences represent the core of the antisense strand of the siRNA duplex. As such, the antisense strand siRNA nucleotide sequences SEQ ID NOs: 10-36 are perfectly complementary to the 3'>5' antisense strand of the target lncRNA. In other words, there are no mismatches between the siRNA and the target.
Applicant is arguing limitations that are not claimed. The examiner did not make an assertion regarding the siRNAs of the specification in comparison to the teachings of Elbashir et al., but the rejection is rather based upon the fact that the claims are not limited to such. The claims are directed to delivery of any RNA-targeting therapeutic. Even with regards to siRNAs, the elected species, the only claim that recites specific sequences is claim 12. The siRNAs of claims 1 and 8 are not required to have any specific structural requirement to any specific target sequence to result in the required function. The claims are not limited to the species of the specification that are argued by applicant. With regards to claim 12, the claim was not previously rejected as it overcomes the written description rejection with regards to the elected siRNAs targeting TROLL-2 by reciting specific siRNA sequences. However, the claim is now rejected because it does not limit the additional RNA-targeting therapeutic to having any specific structure with respect to any specific target sequence and claim 1 has been amended to require knockdown of two or more of the lncRNAs.
The comparison of the siRNAs of instant claim 12 to the TROLL-2 (RPSAP52) sequence published as Genbank Accession No. NR_026825.2 is not commensurate in scope with the instant claims.
Recitation of “RNA-targeting therapeutics for knocking down expression” of the instantly recited lncRNAs encompasses an enormous possible genus of agents wherein the specification does not adequately describe the structure required for the agent to function as claimed.
Claims 1, 2, 5, 8, 12, 21, and 22 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 a method of inhibiting a TROLL-2 sequence via delivery of a TROLL-2 specific shRNA, does not reasonably provide enablement for a method of treating any possible cancer via knocking down the expression of any TROLL-2 sequence with any RNA-targeting therapeutic. 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 a determination of lack of enablement 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)
The claims are directed to a method of treating any possible cancer via knocking down the expression of any TROLL-2 sequence and any of the additional recited lncRNA sequences via broad systemic delivery of any RNA-targeted therapeutic.
The specification does not draw an adequate nexus between knockdown of any TROLL-2 sequence and any of the additional recited lncRNA sequences via broad systemic delivery of any RNA-targeted therapeutic and the predictable outcome of the treatment of any possible cancer, which encompasses an enormous genus of cancers that have not been shown to be reliant upon TROLL-2 in combination with any of the other recited lncRNA expression alone.
The specification demonstrates “shRNA for TROLL-2” delivery, but is silent as to the sequence of the shRNA or the specific TROLL-2 target in breast cancer, lung cancer, and melanoma in tumor xenografts in mice. Mice were fed doxycycline containing food to induce the expression of the shRNA to target the lncRNA TROLL-2 (page 54). The resultant inhibition of this TROLL-2 isoform via shRNA specifically targeted to it in these cancers is not enabling for a method of treating any cancer via knocking down the expression of any TROLL-2 sequence with any RNA-targeting therapeutic.
Importantly, the specification is silent as to the effect of the shRNA targeting the TROLL-2 sequence in any specific cancer. The TROLL-2 inhibition is not representative of treatment of any possible cancer or any possible metastatic cancer or any possible breast cancer, lung cancer, ovarian cancer, colon cancer, or melanoma, or any of these that are regulated by Tap63 in any manner, via inhibition of TROLL-2 alone via any means of knocking down the expression with any RNA-targeted therapeutic.
The specification discloses that certain lncRNAs are “Tap63 regulated”, but does not demonstrate a predictable method of treating any Tap63 regulated cancer (claim 5) of claim 2 via knockdown of expression of any TROLL-2 sequence in combination with any other of the instantly recited lncRNAs.
With regards to instant claim 12, the specification does not draw an adequate nexus between administration of the recited siRNAs and the treatment of any possible cancer. The siRNAs target the “RPSAP52/NR_026825.2 isoform”, which has not been adequately correlated to the presence of any cancer and its inhibition has not been adequately correlated to the treatment of any cancer.
There is no guidance in the specification as filed that teaches how to knock down the expression in any manner of any TROLL-2 sequence in combination with any of the other recited lncRNAs in vivo with the predictable outcome of treating any possible cancer.
With regards to siRNAs, the elected species, the siRNA is not required to have any specific structural relationship to any specific TROLL-2 or lncRNA sequence. Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
Fujita et al. (Int. J. Mol. Sci. 2015, 16, 5254-5270) teach that two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications (page 5254). Fujita et al. teach that the success of an RNAi-based therapy in clinical trials rests on careful selection of target genes and miRNAs. Moreover, we suggest that a delivery route, sophisticated delivery carriers, chemical modification, and modified RNAi platforms are needed to enhance RNAi effects in cancer cells (pages 5262-5263).
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art for therapeutic in vivo applications. 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 mediating RNA interference encompassing in vivo effects.
MPEP 2164.01:
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a):
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).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether knocking down the expression via any manner of any TROLL-2 sequence in combination with any of the other recited lncRNAs in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of any possible cancer. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target and the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. 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.
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 (see MPEP 2164.01(a)).
Response to Arguments
Applicant argues that as at least 3 putative siRNA sequences were disclosed for each of TROLL-1, TROLL-2, TROLL-3, TROLL-4, TROLL-5, TROLL-6, TROLL- 7, and TROLL-8, Applicant provided the requisite teaching to a person of skill in the art to find and select sequences for shRNA, as well as other RNA-targeting therapeutics, for targeting the IncRNAs as currently claimed. The species are not commensurate in scope with the instant claims.
The specification does not clearly define “RNA-targeting therapeutics”, but rather gives examples as set forth in instant claim 8. Even these examples are not required to have any specific structural relationship to any specific target sequence. For example, the claims encompass siRNAs that have a complementary strand to and are targeted to any possible target that has the effect of knocking down TROLL2. Additionally, small molecule inhibitors, peptides, ribonucleases, antibodies, aptamers, and riboswitches can be RNA-targeting therapeutics. Certainly the specific siRNAs of the specification argued by applicant are not enabling for delivery via any means of any possible RNA-targeted therapeutic for knocking down expression of TROLL-2 and any of the other recited lncRNAs as claimed and treating any possible cancer.
Applicant argues that in situ hybridization for TROLL-2 and TROLL-3 revealed increased expression of these lncRNAs in 378 tumor specimens (51 ovarian, 73 colon, 55 lung, and 199 melanoma cases), correlating with higher tumor grade (FIGs. 9B-9G, 10A-10X). To verify this, Applicant showed that shRNA-induced downregulation of TROLL-2 and TROLL-3 in two different orthotopic models of lung adenocarcinoma and two different melanoma xenograft models strongly impaired tumor formation in all models tested (see FIGs. 9H-90). These data demonstrate that TROLL-2 and TROLL-3 are markers of cancer progression and are necessary for tumor and metastasis formation in multiple cancer types (see, e.g., paragraph 75 on page 42 of the present application as originally filed).
Contrary to applicant’s arguments, this disclosure of the specification demonstrates that knockdown of TROLL-2 and TROLL-3 is enabling for inhibition of two species of cancer cells, but is not enabling for broad systemic delivery of any RNA-targeted therapeutic, each having their own d3elivery challenges, that knocks down the expression of any of the two recited lncRNAs and the predictable treatment of any possible cancer.
Increased expression of a transcript in 378 tumor specimens (51 ovarian, 73 colon, 55 lung, and 199 melanoma cases) is not demonstrative of inhibition of the lncRNA and the predictable treatment of each of the cancers. The specification does not demonstrate that any possible cancer is dependent upon expression of TROLL-2 in combination with any of the other recited lncRNAs alone.
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.
Claim(s) 1, 2, 5, 8, 21, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Helgason et al. (US 2018/0051340 A1), in view of Oliveira-Mateos et al. (Nature Communications, 2019, 10, 3979, 1-18), and Huang et al. (ONCOLOGY REPORTS 40: 2683-2689, 2018).
The references are considered as enabled as the instant claims.
Helgason et al. teach that RSAP52 (the TROLL-2 isoform recited in previously recited claim 11) is upregulated in metastatic prostate cancer (Table 4, page 19) (instant claim 22).
Helgason et al. teach that this lncRNA may be used in combination with PCAT18 to treat prostate cancer (page 18). Helgason et al. teach a method of administering an inhibitor of PCAT18 to treat prostate cancer and that PCAT18 is a lncRNA upregulated in prostate cancer (abstract and Figures).
Helgason et al. teach silencing of PCAT18 using PCAT18 siRNAs (Example 5, pages 30-31).
It would have been obvious to treat metastatic prostate cancer in a subject having metastatic prostate cancer via knocking down the expression of TROLL-2 (isoform RPSAP52) with a TROLL-2 targeted siRNA because Helgason et al. teach siRNA inhibition of an upregulated lncRNA (PCAT18) to treat prostate cancer and teach that RSAP52 is another lncRNA upregulated in metastatic prostate cancer and teach that both lncRNAs can be used in combination for the treatment method (instant claims 1, 8, and 21). Additionally, the sequence of a species of RSAP52 was known, as evidenced by Oliveira-Mateos et al. (RPSAP52 transcript NR_026825.2, pages 2 and 15).
Helgason et al. do not offer motivation to knock down the expression of RPSAP52 to treat breast cancer. However, Helgason et al. does offer motivation to inhibit the expression of an upregulated lncRNA for the treatment of the cancer.
Oliveira-Mateos et al. teach that RPSAP52 is overexpressed in breast cancer (page 2, column 1) (instant claim 2). It would have been obvious to utilize a siRNA targeting RPSAP52 to knock down the expression of RPSAP52 to treat breast cancer because Helgason et al. offers motivation to inhibit the expression of an upregulated lncRNA for the treatment of the cancer; and teaches utilizing siRNAs targeting lncRNAs; and teaches that RPSAP52 is upregulated in prostate cancer and can be used in the method to treat prostate cancer.
Oliveira-Mateos et al. teach that upon RPSAP52 knockdown, all three breast cell lines tested (the non-transformed MCF10A and the tumorigenic Hs578T and HCC1143 cells) proved to be significantly less proliferative (page 4, column 1) (instant claim 2).
It is noted that instant claim 1 recites that the instant lncRNAs are Tap63-regulated. Therefore, the cancer meets the limitation of being Tap63-regulated (instant claim 5) by being treatable by inhibition of the lncRNA.
It would have been obvious for the cancer to already be established in the human because treatment of cancer requires the presence of the cancer (instant claim 21).
It would have been obvious to inhibit MALAT1 (TROLL-7) in the same method of treating breast cancer because Huang et al. teach that MALAT1 promotes angiogenesis in breast cancer. Huang et al. teach: Then, we knocked down endogenous MALAT1 in MCF-7 cells using MALAT1 short hairpin RNA (shRNA). The results revealed that MALAT1 knockdown could significantly inhibit proliferation, migration, and tube formation in vitro (abstract).
Therefore, it was known that knocking down TROLL-2 and knocking down TROLL-7 treats breast cancer. It would have been obvious to combine the two because each have the same intended purpose of the treatment of the same cancer. It would have been obvious to utilize a siRNA as the inhibitor, as siRNAs are known lncRNA inhibitors, as taught by Helgason et al. and because Huang et al. teach utilizing shRNAs to knockdown TROLL-7.
It is noted that the rejection is directed to delivery of siRNAs that target specific sequences taught by the cited references to treat a specific disease state.
Response to Arguments
Applicant argues that there is only a single mention of TROLL-2 in Helgason as RPSAP52, where its deregulated expression is found in common with 229 other RNAs. No other TROLL lncRNAs are disclosed in Helgason. Helgason provides no specific motivation to target TROLL- 2 (RPSAP52) either, merely alleging that any one of the 230 lncRNAs "may be used in combination with PCAT18 in order to diagnose or treat prostate cancer using the methods as described herein." (see Helgason, page 18, paragraph [0177]). Helgason does not provide a single experiment showing the effect of knocking down expression of any one of these additional 230 lncRNAs, let alone RPSAP52. The reference is not required to only teach TROLL-2. Each of the lncRNAs taught by the reference are equally obvious to try.
Applicant respectfully submits that the claimed combination was not taught or suggested by the cited art, and it was only with the benefit of improper hindsight reasoning after review of the disclosure of the present disclosure that a rejection was formulated.
The basis of this assertion is unclear because the primary reference offers motivation to inhibit TROLL-2 to treat a cancer and to inhibit lncRNAs with siRNAs and Oliveira-Mateos et al. teach that upon RPSAP52 knockdown, all three breast cell lines tested (the non-transformed MCF10A and the tumorigenic Hs578T and HCC1143 cells) proved to be significantly less proliferative (page 4, column 1) (instant claim 2). It would have been obvious to utilize a siRNA, a known tool for inhibiting lncRNAs with known sequences, to inhibit the specific TROLL2 sequence taught by Oliveira-Mateos et al. given that the reference teaches that knockdown of the target treated breast cancer. No impermissible hindsight was required for this straightforward analysis.
Applicant argues that the references teach that the claimed method would not work for the reasoning proposed by the Examiner, but does not explain this assertion. There is no teaching in either of the references that inhibiting TROLL-2 would not treat a cancer.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 5, 8, 21, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 8, 14, and 15 of copending Application No. 18/277,760 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of application ‘760 are directed to a method of treating cancer via administering an anti-cancer agent, wherein the instant agent for knocking down TROLL-2 is an anti-cancer agent, and wherein the claims of application ‘760 require assaying for TROLL-2 expression before administration of the agent. Assaying for expression of the target that is the same target as instantly recited would be an obvious step to incorporate into the instant method given that the purpose of the instant method is to inhibit TROLL-2. One would want for TROLL-2 to be expressed in order to inhibit it. The claims of application ‘760 recite that the agent is a siRNA that targets TROLL-2 and wherein the cancer is TAP63 regulated and wherein the cancer is breast cancer. The claims are obvious variations of each other. The only difference is the addition of the step to confirm expression of the intended target.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 5, 8, 21, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7 and 21 of copending Application No. 17/791,706 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of application ‘706 are directed to a method of treating cancer via administering an anti-cancer agent, wherein the instant agent for knocking down TROLL-2 is an anti-cancer agent, and wherein the claims of application ‘706 require assaying for TROLL-2 expression before administration of the agent. Assaying for expression of the target that is the same target as instantly recited would be an obvious step to incorporate into the instant method given that the purpose of the instant method is to inhibit TROLL-2. One would want for TROLL-2 to be expressed in order to inhibit it. The claims of application ‘706 recite that the cancer is TAP63 regulated and wherein the cancer is breast cancer. The claims are obvious variations of each other. The instant agents are species of the genus of application ‘706. The specification of application ‘706 defines the agent as including siRNAs. The only difference is the addition of the step to confirm expression of the intended target.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
Prosecution Insights