DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to an amendment filed 12/15/2025.
Claims 1, 2, 4-7, and 9-23 are pending.
The instant application is a 371 filing of PCT/EP2020/079022 filed 10/15/2020 which claims priority to EP 19203627.5 filed 10/16/2019.
Information Disclosure Statement
An IDS filed 12/15/2025 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action. Initials indicate that the document has been considered even if the reference is lined through.
Response to Amendments
The objections to the drawings are overcome by amendment. The objections to the claims have been overcome by amendment. The amendments are sufficient to overcome the rejection under 35 USC 112, second and fourth.
Applicants’ amendment to limit the compound to a sequence that consists of SE QID NO:1 overcomes the art. However, as set forth below, such a sequence is not sufficient to promoter expression and /or activity enhancement of the sequence nor to mediate any therapeutic activity.
Specification
The disclosure is objected to because of the following informalities: on page 34, heading of example 6, “microvesicles is misspelled”. .
Appropriate correction is required.
Claim Rejections - 35 USC § 112, first paragraph
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.
Claims 1, 2, 4-7, and 9-23 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is in part a new rejection necessitated by applicants amendment. The claim is amended to provide proper dependency as well as reflected the disposition above.
The claims as amended in a manner which is not supported by the disclosure. Amended claim 1 and 2 from which claims 4-7, 15-18 and 21-23 depend recite a compound that promotes expression and/or activity of the ncRNA consisting go SEQ ID NO:1 or a sequence at least 90% related. (The issue of identity is addressed below with the remaining claims so related). SEQ ID NO:1 is a sequence which in and of itself cannot promote expression or activity of itself. It appears that the claim might intend that the compound promotes expression or activity of SEQ ID NO:1 by expressing the sequence . However, the claim simply recites that the compound is a nucleic acid or expression vector or “host” consisting of SEQ ID NO:1 or a sequence with at least 90% identity thereto. This sequence on its own even if in “an expression vector” does not promote expression or activity. It simply is a sequence. On its own, the nucleic acid sequence linked to a an inducible promoter promotes expression and potentially activity if an inducer is present. Similarly, an expression vector with a constitutive promoter will lead to expression and potentially activity. However, each would require the presence of a host cell or in vitro transcriptional machinery (IVT) to mediate this expression or activity promotion. The inert sequence do not provide these functions.
The disclosure teaches, ncRNA of SEQ ID NO:1 also called circ-Insr or circInsr and was isolated from a screen of healthy versus failing hearts as a dysregulated species. It was cloned into an AAV vector as well as IVT and introduced into cardiac cells and/or mouse models and demonstrated a protective role in cardiotoxicity (example 2, 3, 7 and 8). But, applicants do not teach sequences other than SEQ ID NO:1. Claim 1 and 2 allow for sequences that are 90% related. The disclosure does not teach sequences or domains or regions other than all of SEQ ID NO:1 that provides the heart protective function. However, the claims are drawn to variants of SEQ ID NO:1. These variants are also promoted for expression or activity with the goal of treating or preventing cardiac vascular disease or metabolic disorder or to diagnose HF or a predisposition thereof. Hence, the claims are drawn to a structural molecule that must also have functional properties. However, there is no disclosure of sequences that are variants of SEQ ID NO:1 and provide the required for function. The specification only teaches that SEQ ID NO:1. As well, there is no disclosure of the structural properties that are required of the ncRNA to mediate the required functional properties.
The claims thus are drawn to a large genus which are not sufficiently described in the specification. The written description requirement for genus claims may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with known or disclosed correlations between function and structure, or by a combination of such characteristics sufficient to show that the applicant was in possession of the claimed genus.
Response to Arguments
Applicants argue that the disclosure supports the genus of compounds that are now drawn to compounds that promoter expression and/or activity of SEQ ID NO:1 (ncRNA or circ-INSR). Applicants point to examples 6-8. The compound is firstly an inert molecule, it is a sequence. The sequence is the same as the one to be expressed or once expressed the sequence which activity is to be enhanced. The sequence does not have this capacity. Example 6 teaches the ability to express circINSR from a plasmid in a cell line. Example 7 teaches IVT which simply increases the concentration of the product in a sample. Example 8 teaches that treatment of cells with anthracyclines appears to have been decreased. No where does this teach either the structure function of SEQ IDNO:9 such that variants with 10% variability can be identified nor does it support a compound which enhances its own expression and/or activity.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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 2, 9-14 and 17-23 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for 1) a method of treating a cardiovascular disorder in a subject comprising anthracycline induced cardiotoxicity associated with decreased circ-INSR by administering directly to the heart an AAV vector comprising a nucleotide sequence encoding SEQ ID NO:1 operably linked to a heart specific promoter wherein the sequence complements the deficiency and 2) a method of detecting the presence of the RNA sequence of SEQ ID NO:1 in a sample from a subject, does not reasonably provide enablement for any other embodiment. 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 use the invention commensurate in scope with these claims. This rejection is necessitated in part by applicants amendment to alter claim 2 to a method of treating and/or preventing cardiac vascular disorder or metabolic disorders. The remaining part of the rejection are maintained from the previous office action.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to method of preventing, treating or diagnosing heart failure. The methods are also drawn to a method of diagnosing heart failure or a predisposition to heart failure in a patient by detecting the level of ncRNA to a healthy subject or a predetermined standard.
2) Scope of the invention. The scope of the invention is extremely broad in that the method of therapy is directed at treating or preventing a cardiac vascular disease or metabolic disorder wherein the steps are simply administering a compound that promotes expression and/or activity of the ncRNA consisting of the nucleotide sequence of SEQ ID NO:1. This compound can be the nucleic acid sequence, an expression vector or host comprising thereof of SEQ ID NO:1.
The method also calls for diagnosing predisposition of HR. The method simply requires detecting the presence of the ncRNA encoded by SEQ ID NO:1 but as well that of a sequence with 90% identity. It is indicative if it is greater than 2 fold downregulated from “a healthy subject” or a “predetermined” standard.
3) Number of working examples and guidance. SEQ ID NO:1 is a non-coding RNA (ncRNA). It is also called circ-INSR. It was isolated from a screen of healthy versus failing hearts as a dysregulated species (Example 1). The specification alleges that it functions to maintain mitochondrial function in cardiomyocytes. In doxorubicin treated mice, the level of ncRNA was downregulated and overexpression of this circINSR attenuated apoptosis in isolated neonatal rat cardiomyocytes. circINSR was cloned into an AAV9 vector as well as IVT and introduced into isolated cardiac cells and/or mouse models and demonstrated a protective role in cardiotoxicity (example 3, 7 and 8). Expression of circ-INSR was decreased in the presence of BRCA1 siRNAs (example 4). Mitochondrial stress was enhanced in circ-ISNR siRNA treated cells (example 8) and rescued by treatment with AAV6-circINSR Applicants measured expression in healthy vs injured hearts and determined that the level of circ-INSR was decreased in injured hearts.
[0019] Without wishing to be bound by this theory it is believed that the metabolic protective effect of the ncRNA of SEQ ID NO: 1 is mediated by the binding of the ncRNA to the protein SSBP1 (single-stranded DNA-binding protein 1). The SSBP 1 gene is a housekeeping gene involved in mitochondrial biogenesis. SSBP 1 is known to act as a homotetramer to stabilize the displaced single strand of the normal and expanded displacement loop (D loop) during mtDNA replication, thus preventing formation of secondary single-stranded DNA structures, which could stop the gamma-DNA polymerase.
Thus, applicants propose use of SEQ ID NO:1 as a therapeutic based upon the detection of under expressed levels in tissue samples and mice models induced with cardiotoxicity wherein delivery of circ-INSR to these cells protected mice from cardiotoxicity and protected isolated cells from apoptosis induced by doxorubicin. They thus assert it can be used to prevent or treat cardiac vascular or metabolic disorders of the heart.
4) State of the art. Heart failure is a disorder is a complex condition affecting the cardiovascular system, is the heart’s inability to pump and transport blood and oxygen throughout the body. The variables and risk factors are known but predicting for whom therapy is needed is an ongoing issues (Shrivistrava, page 2, col 1).
A biomarker is defined as a biological compound that is easily accessible and measurable in the body. The biomarker can be classified as molecular, cellular, or imaging as long as they help in identifying the disease or provide therapeutic guidance
Identifying biomarkers is a defined process (Shrivistrava, col 13, col 1).
The identification and further exploration of biomolecules suitable as biomarkers for specific disease is a complex process, which requires numerous prerequisites to be met such as detectability in the circulation, reliable quantification methods, pathophysiologic relation to the suspected disease, and many more
It is noted that applicants own publication published after the effective filing date of the application demonstrates the nascent state of the art. Lu et al, page 4511.
In summary, Circ-INSR rescues doxorubicin-induced cardiac dysfunction and cardiomyocyte apoptosis through interaction with SSBP1, thus maintaining mitochondrial function. Further studies are warranted to develop this novel target and its overexpression strategy into a clinical preventive therapy for patients at high risk for doxorubicin-mediated cardiotoxicity. Altogether, this study reveals Circ-INSR as a promising target.
5) Unpredictability of the art. These results provide proof of principle in the involvement of circ-INSR in cardiotoxicity. From this, applicants claim treatment by administration of a nucleic acid, expression vector or host comprising SEQ ID NO:1 which encodes circ-INSR. As a first issue, the step of preventing cardiac vascular disease or metabolic disorders the claims are also directed to those for whom the disease must be predicting. Predicting the subjects that would require treatment is considered highly unpredictable. In humans, the claimed diseases are usually established before therapy is offered. The specification does not adequately teach how to effectively predict for whom prevention would be required. One establishes a large genus of target subjects for whom the method is intended, however, establishing whether a person or persons actually requires the treatment is a highly unpredictable art. Screening procedures for indications of those requiring inhibition of the onset of disease are unknown and highly prejudicial leading to conditions in which those who require the treatment cannot be distinguished from those who do not. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, applicants exacerbate the unpredictability of the art by reciting subjects to be targeted for whom the disease must be prevented.
Considering more generally the method of treating disease with gene therapy, there are numerous obstacles that render the claim as recited highly unpredictable. The art teaches that there are formidable challenges to gene delivery (see Kim et al Circulation, 2024, abstract).
However, effective delivery of gene therapy to specified cells presents formidable challenges. Viral vectors, notably adeno-associated viruses and nonviral vectors such as lipid and engineered nanoparticles, offer distinct advantages and limitations. Additional risks and obstacles remain, including treatment durability, tissue-specific targeting, vector-associated adverse events, and off-target effects.
This is compounded by the broad recitation of nucleic acid. It has been found that for delivery of genes, there must be protection against the immune system as well as degradative processes in vivo. As well, the nucleic acid is simply administered to the subject and there must be means of targeting the disordered organ (see Kim et al, page e472, col 2). This is true of the expression vector. It is noted that even though it is called an expression vector, it, like the nucleic acid and hence the host, do not have means of expressing the sequence. There simply is limited means to overcome the obstacles i.e. organ barriers, failure to persist, side-effects in other organs, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived (see Kim et al, bridging ¶ page e475 and e477 as well as page e477 col 1 and page 566, Lee et al, YMJ, 2024). Naked nucleic acids have not worked and finding an ideal vector has been limited.
In most clinical studies, the genetic factor concentration delivered to the target tissue failed to reach the therapeutic level. Various non-viral vectors, including polymers, have been tested in gene therapy. Although several non-viral vectors have been successful in preclinical research, none of them showed more effectiveness than viral vectors for gene delivery. High transfer efficiency and durability are the basic essentials for the success of gene therapy. The transgene expression of a non-viral vector lasts up to 4 weeks, the lifespan of the transfected cell. Therefore, to date, viral vectors are still preferred due to longer gene expression. However, there are also several limitations in viral gene transfer. Although Ad has a strong tropism for cardiomyocytes and provides high gene expression to the therapeutic level, repeated administration could evoke the humoral or cellular immune response, limiting the expression of the transferred gene and shortening the transgene expression. The third-generation Ad would be promising due to less immunogenicity and long-lasting gene expression.
AAV has been promising but requires direct administration (Lee et al, page 567, col 1).
However, systemic leakage of gene transfer and provoked immune response are also the big issues of AAV vector. Systemic leakage of the vector with angiogenic gene factor leads to various harmful off-target effects, such as tumor growth, tissue edema, and retinal problems. To overcome the issue regarding off-target effects, many researchers have developed various gene delivery methods to the cardiovascular system. Local injection of gene product with sophisticate instrument, NOGA catheter, can provide accurate gene transfer to the target structure while minimizing systemic leakage.38,96
Finally, the claims as set forth in the written description rejection do not provide a composition that can promote expression and/or activity of ncRNA.
Considering the obstacles identified in using ncRNA, Poller discuss the use of ncRNA in cardiovascular diseases (Eur Heart, 2018) wherein reliance on animal models as done in the disclosure is not a valid indicator of success.
(bridging ¶, page 2710-2711). Whereas animal studies are most valuable and indispensable for proof of principle, most of these studies use young otherwise healthy animals and thus rarely reflect the clinical reality. Taking HF as an example, few if any animal models mimic the human HF reality, a chronic systemic condition lasting years to decades. Models of chronic HF in animals are rare and only recently a model emerged which combines diabetes, obesity, hypertension, and leads to kidney dysfunction.210,211 On the solid foundation of animal studies, few pioneering clinical trials were successful in demonstrating the technical and clinical feasibility of ncRNA therapeutic approaches.
These all demonstrate the lack of predictability of the broad genus of disorders to treat or prevent.
The use of circular RNAs as biomarkers is discussed in the art and found to be fraught with obstacles (Shrivistrava, page 12, col 2).
Sequencing data revealed more than 15,000 circRNAs present in the human heart, some in high abundance (224). A number of studies have described cardiac circRNAs to be involved in MI-related apoptosis in the myocardium (225, 226) and circRNA MICRA was identified to predict left ventricular dysfunction in MI patients (227). The results were validated in a different study where circRNA MICRA was reported to improve risk stratification of post- MI patients (228). Recently, cardiac circRNAs were assessed for their detectability in the circulation after MI in a controlled stepwise approach (74). Interestingly, none of the screened and validated circRNAs were identified as well-enough detectable in neither plasma nor serum to be used as circulating cell-free biomarkers. The findings question the validity of quantifying circulating circRNAs in cell-free body liquids using currently available technology. In fact, when studying literature regarding circulating circRNAs including the abovementioned studies regarding circRNA MICRA, an interesting fact can be observed: all circulating circRNA biomarker studies report their findings in whole blood samples—containing a large number of circulating cells instead of cell-free serum or plasma. The use of whole blood samples in the assessment of disease biomarkers yields a risk of confounding by cells such as platelets and leukocytes. Thus, the assessment of circRNAs as circulating biomarkers in CVD currently suffers from detectability problems and efforts to improve detectability are needed to further evaluate this issue.
The issues are summarized on page 13, table 2 wherein the fitness of ncRNA as a biomarker is not found.
6) Undue experimentation. Hence, the claims reading on significant numbers of inoperative embodiments would render claims non- enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative. Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298,302 (CCPA 1971). (see MPEP 2164.08(b)
The invention recites use of a broad group of. Given the unpredictability of the art, the poorly developed state of the art with regard to predicting the structural/ functional characteristics of antagonists, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.
Response to Arguments
Applicants argue that the means of detecting circINSR are within the skill of the art. This is not the issue. The issue is what are the predetermined standards. As well, applicants claims use of healthy subjects controls samples wherein a greater than 2-fold downregulation of SEQ ID NO:1 indicates heart failure or a predisposition of HF. However, this is simply conjecture. There is no evidence that these standards provide the level of diagnosis required to diagnose HR or the potential thereof. Poller et al provides a clear set of standards used to identify cardiovascular disease (see page 2714, col 2).
Implementation of new biomarkers into clinical practice is an important area of biomedical research. Non-coding RNAs are in particular considered as potential biomarkers if they meet the following criteria: (i) they are quantitatively altered in cardiovascular disease (CVD),223,224 (ii) they show organ- and cell-specific expression patterns225 and thus can act as indicators of specific pathogenic processes,14 (iii) they are easily accessible,226 and (iv) they withstand conditions such as storage, multiple freeze/thaw cycles and different pHs,227 show a high degree of stability in body fluids228 (Box 3).
In this case, this is exacerbated by the reliance on a standard that is listed as predetermined or 2 fold reduced compared to a healthy human. Challenges using biomarkers are plagued by standards (Poller European Heart J, 2018, page 2716, col 1).
The choice of material (serum, plasma, urine, cells) needs to be considered as alterations in ncRNA levels between these materials have been found. miR levels can greatly vary between serum and plasma,260 and material-dependent stabilities were found for lncRNAs CoroMarker and LncPPARd between PBMCs and plasma.261 In addition, heparin administration prior to blood sampling, haemolysis of blood cells, and intake of medication have been shown to interfere with results of miR quantification.262,263 Moreover, non-cardiac diseases and phenotypes may influence the circulating levels.264,265 Methodological issues are another ongoing challenge to cope with: RNA yield greatly varies between different isolation procedures.
Applicants reliance on mouse and cell culture results to determine that circ-INSR could function as a diagnostic for HF or the potential thereof is a broad unsupported claim.
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 MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
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, Maria Leavitt can be reached at 571-272-1085. 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.
/MARIA MARVICH/Primary Examiner, Art Unit 1634