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 9/12/2025.
Claims 19-23, 26-30 and 33-40 are pending.
This application is a 371 filing of PCT/ES2020/070315 filed 5/15/2020 which claims priority to Spanish applications ESP201930427 and ESP201930428 both filed 5/15/2019. All of the prior art documents are provided in English.
Response to Amendments
Applicants have submitted digital drawings and replacement drawings that are sufficient to overcome the objections to the drawings. The previous objections have been overcome as have the rejections under 35 USC 112, first.
Claim Objections
Claims 21 and 30 are objected to because of the following informalities: “vector” in claim 21, line 3 requires an article “a” prior to it. This is true of claim 30.
Appropriate correction is required.
Claim Rejections - 35 USC § 112, second paragraph
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19-23, 26-30 and 33-40 are vague and indefinite in that the metes and bounds of the composition are unclear. The dependent claims are included in the rejection because they fail to address or clarify the basis of the rejection as discussed in detail for the independent claims. These rejections are new based upon amendment.
Claim 19 recites that it comprises an isolated RNA or DNA polynucleotide wherein the claim continues that this DNA or RNA has an identity of at least 80% to 99% to the nucleotide sequence of SEQ ID NO:1 or the composition comprises an isolated RNA polynucleotide that encodes a nucleotide sequence of having the identity with the nucleotide sequence of SEQ ID NO:1. First, the claim is redundant in the mention of RNA as having the sequence of SEQ ID NO:1 and then again as encoding it. The duplicate mention in claim 19 line 3 and 10 is confusing. It is unclear if this is intended or a mistake. As an initial issue, RNA cannot have the nucleic acid sequence of SEQ ID NO:1 as SEQ ID NO:1 is a DNA sequence. But, as well, RNA does not encode DNA. The claim is entirely too confusing as to what is in the composition. It is noted that the phrasing that the polynucleotide has “an identity” is not consistent with common reference. Typically, the claim would recite that the polynucleotide has at least 80%.... identity to the nucleotide sequence of. The issues are relevant as regards claim 26, claim 34, claim 37-39 which each recite that the polynucleotide encodes SEQ ID NO:1 (a DNA sequence).
Claim 21 as amended is unclear. First, there are two nucleotide sequences previously referenced- the nucleotide sequence of SEQ ID NO:1 and the hybrid nucleotide sequence. Hence, reference to “the nucleotide sequence” in line 5 does not indicate to which the claim refers. Secondly, the claim is confusing as it recites in part b) a combination of the DNA and the hybrid. But, the hybrid already comprises the DNA polynucleotide sequence.
Claim 21b) is confusing as the new language that the nucleotide sequences is “corresponding to” a gene expression system or a vector. It is unclear how the hybrid DNA comprising the DNA polynucleotide can correspond to a system or a vector. As such the amended claims has issues of metes and bounds are also raised here as it is not clear how close to an expression vector or system the hybrid sequence as claimed must be to correspond to one. This has issues relevant for claim 30, 35 and 40 as related to the DNA corresponding to a system/vector.
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 19-23, 26-30 and 33-40 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of treating breast cancer, colon cancer or cervical cancer in a small animal model, the method comprising intratumoral administration of a composition comprising a DNA comprising the nucleotide sequence of SEQ ID NO:1 and/or SEQ ID NO:2 or an RNA encoded from these sequences to the cancer wherein the DNA sequence is operably linked to a promoter, 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 maintained but amendment based upon applicants’ amendment.
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 treating a cancer with a nucleic acid molecule that encodes a sequence at least 80% related to SEQ ID NO:1. Hence, the invention is rooted in gene therapy.
2) Scope of the invention. The scope of the invention is extremely broad in that the composition is a broadly claimed DNA sequence with at least 80% to SEQ ID NO:1 or SEQ ID NO:2 or an RNA encoding thereof. This is a large genus of sequences in that over 32 of the 156 nucleotides of SEQ ID NO;1 and 21 of the 108 of SEQ ID NO:2. The composition is administered by any means used to “treat” a subject with breast, colon or cervical cancer. The method based on suicide gene therapy is known to be a highly unpredictable art.
3) Number of working examples and guidance. The specification is primarily prophetic. The proliferative disease is newly limited to breast, cervical or colon cancer. To this end, applicants propose use of two bacterial toxin/antitoxin modules (TA) called hokD (SEQ ID NO:1) and ldrB (SEQ ID NO:2).
[0030] The inventors have selected two genes, hokD and ldrB, to study their behavior in eukaryotic cells, since they may be possible new candidates for being used in the suicide gene therapy in cancer given their many qualities in causing death in the host cell.
These were analyzed in vitro for anti-proliferative effects in HCT-116, MCF7 and HeLa cells. These results were reiterated in tumor xenograft mice for breast, colon and cervical cancer cell lines.
4) State of the art. Gene Therapy is the method by which the nucleotide sequence of SEQ ID NO:1 is delivered to the subject for the purposes of treating the breast, colon and cervical cancer. The instant claims broadly recite administering the claims. The art teaches that delivery of nucleotide sequences occurs by many platforms including non-viral and viral. As claimed, delivery is not specified and hence encompasses any and any mode of administration. There are many reviews on the progress in this art wherein the ultimate, the challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. 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 as to delivery vector and mode of administration (Al-Dosari and Gao). Especially, it is noted that the target disease, organ and delivery vector is a factor that impacts the ability to get to levels of expression needed for therapy (see Fumoto especially section 3 and 5).
5) Unpredictability of the art. The issues that remain are reorganized below based upon applicants’ amendment. First, the invention is directed to gene therapy of cancer using a composition that is defined only by containing nucleotide sequences. While the disclosure demonstrates proof of principle, the obstacles for clinical use are clear in gene therapy. The art known methods for administration of nucleotides is highly unpredictable. For breast, colon and cervical, it has been shown that these must be administered directly (see Aznar i.e. page 33, col 1 and Fumoto et al, page 11). There simply is no other way 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 challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. 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. This is extremely complicated by the fact that the genes delivered are suicide genes which must be restricted to the cancer. Off target delivery will have profound effects.
This is complicated by the fact that in vitro and animal models did not correlate with human therapy when considering the physiology of the two. The results from comparing results in humans and in animals demonstrates that there is little correlation between the two (Shanks, 2009, pages 6 and 7).
As you can see there is little correlation between animal and human data. In some cases human bioavailability is high when bioavailability in dogs is high but in other cases dogs and humans vary considerably. The patterns exhibited by both are what are frequently referred to as a shotgun pattern; meaning that if one fired a shotgun full of bird shot at a target one would see the same pattern. No precision and no accuracy. The pattern is also referred to as a scattergram, meaning that the pattern is what one would expect from random associations.
Howard Jacob notes that rats and humans are 90% identical at the genetic level. however, the majority of the drugs shown to be safe in animals end up failing in clinical trials. "There is only 10% predictive power, since 90% of drugs fail in the human trials" in the traditional toxicology tests involving rats. Conversely, some lead compounds may be eliminated due to their toxicity in rats or dogs, but might actually have an acceptable risk profile in humans [39]. (Emphasis added.)
This leads to a third issue for which mice models have not proven corelative and have led to the lack of successful translation from mice to clinic.
Fourth, as to nucleic acids that are 80% identical to SEQ ID NO:1 and 2, consideration is not CAN applicants screen all of potential sequences to find those that are functional but does the art and/or applicants’ disclosure provide adequate guidance on how to find those sequences. In this case, it is unclear what domains/sequences are necessary for applicants’ invention to function. The claims require knowledge of regions within each of SEQ ID NO:1 and 2 which can be modified and must not be modified AND still allow the molecule encoded by the sequence to treat cancer. The specification does not define domains or nucleotides that mediate this activity. To put this in perspective, to be 80% identical to SEQ ID NO:1, 21 nucleotides can be altered. The predictability of modifications of for example 21 different combinations of amino acids mutated in SEQ ID NO:1 and for SEQ ID NO:2 with different modifications requires testing of a large genus of molecules for functionality in the absence of a clear understanding as to which nucleotide sequences tolerate change.
The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one skilled in the art could make and use the entire scope of the claimed invention without undue experimentation.
The lack of adequate description of a variety of the required limitations compounds the lack of predictability if the art of gene therapy. One cannot use what one cannot envision. The relationship of enablement with the requirement for written description is acknowledged by the MPEP as well as the courts (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly& Co., 43 USPQ2d 1398 (CA FC, 1997)).
Hence, it is the art acknowledged lack of correlation in combination with the complexity of this art and the scope of the steps that makes the lack of relevant correlation important. Therefore, animal models have allowed proof of principle issues to be established. In patent prosecution, this is relevant wherein the ability to establish a correlation is necessary.
6) Undue experimentation. By claiming the invention broadly and because of the lack of description thereto for the genus claimed, the method does not provide sufficient guidance to overcome art recognized obstacles for in vivo delivery. In the absence of such guidance, one must rely on the art known methods. 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, the disease is broadly stated and the method simply as being administered.
The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. The invention recites use of a broad group of sequence. 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
The issues that remain are based in the large breadth of the claims in light of the lack of predictability of the art. Specifically, the disclosure lacks specificity as to how the obstacles of delivery of any DNA or RNA as well as RNA can be delivered to the target cells such that activity desired can follow. As well, the claims embrace an extremely large genus of DNA sequences. To this applicants argue the following. First as to delivery issues raised above, applicants argue that one could use routine optimization to implement the methods. The issue with gene therapy is not optimization but practicality. The means to deliver DNA and/or RNA to a subject such that the DNA/RNA reaches the target without being subjected to immune degradation, sequestration or off target localization. With naked DNA/RNA as recited, the biggest issue is degradation which would be expected to occur immediately upon administration. With suicide genes, the delivery only to targeted cancer cells is not guaranteed and certainly not possible as described. As applicants provide no explicit means to deliver, it is not clear what is envisioned. Hence, one cannot determine how to overcome the issues of delivery that are not straight forward in the art. This is severally complicated by the fact that the encoded genes in their core are suicide genes. These molecules must be guarded against off target delivery.
Secondly, applicants argue that with codon degeneracy the nucleotide identity range would fall in 80% to 99%. However, the claim extends beyond codon degeneracy and reads on sequence variants. As set forth above the disclosure does not provide adequate description of variants such that a person of skill in the art would know what sequences can be varied. Structural features that could distinguish the compounds of the claimed genus from others not encompassed by the genus are missing from the disclosure. In this case, there are specific elements referenced but the claims reference these structures with broad generic functional terms that represent a large and diverse genus of elements. To this end, the MPEP provides such guidance (emphasis added). If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art). As recited, the method lacks critical elements that provide necessary function.
Double Patenting
A rejection based on double patenting of the "same invention" type finds its support in the language of 35 U.S.C. 101 which states that "whoever invents or discovers any new and useful process ... may obtain a patent therefor ..." (Emphasis added). Thus, the term "same invention," in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957); and In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970).
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. See 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);and, 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) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 19-32 are provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1, 2, 5, 6 and 8-14 of copending Application 18/704,750. Because rejections remain, this rejection is maintained.
Because none of the applications have restriction requirements present, there is no prohibition against double patenting.
Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims recite compositions and methods of treating a proliferative disease using hokD and/or ldrB. The difference between the two is that the instant claims use the SEQ ID NO:1 while the copending claims refer to the sequence by name. It would have been obvious to one of ordinary skill at the time of the invention was made to use the disclosed sequences which are present in both applications as SEQ ID NO:1 and 2. Specifically copending Application 18/704,750 discloses that hokD and ldrB are inherently SEQ ID NO:1 and 2. Based upon the teachings of the cited references, the high skill of one of ordinary skill in the art, and absent evidence to the contrary, there would have been a reasonable expectation of success to result in the claimed invention.
Additionally, if a patent resulting from the instant claims was issued and transferred to an assignee different from the assignee holding a patent from copending Application 18/704,750, then two different assignees would hold a patent to the claimed invention of copending Application 18/704,750, and thus improperly there would be possible harassment by multiple assignees.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
Prior art identified but not cited US 20190169623, Starlz et al.
SEQ ID NO:2 sequence is disclosed as a cell death gene (SEQ ID NO:127) by Starzl, ¶0080). However, this sequence is not cited for use in proliferative disorders and there is no evidence that HokD is known to be used in proliferative disorders.
0080] In some embodiments, the synthetic microorganism comprises a kill switch molecular modification comprising a cell death gene selected from the group consisting of sprA1, sprA2, kpn1, sma1, sprG, relF, rsaE, yoeB, mazF, yefM, or lysostaphin toxin gene. In some embodiments, the cell death gene comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 122, 124, 125, 126, 127, 128, 274, 275, 284, 286, 288, 290, 315, and 317, or a substantially identical nucleotide sequence.
SEQ ID NO 127 <211> LENGTH: 156 <212> TYPE: DNA <213> ORGANISM: Escherichia coli <400> SEQUENCE: 127
atgaagcagc aaaaggcgat gttaatcgcc ctgatcgtca tctgtttaac cgtcatagtg 60
acggcactgg taacgaggaa agacctctgc gaggtacgaa tccgaaccgg ccagacggag 120
gtcgctgtct tcacagctta cgaacctgag gagtaa 156
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.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634