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 claims filed 3/20/2026. Claims 1-11, 20, 21 and 27-44 are pending.
This application is a continuation of U.S. Application No.: 15/383,452 filed on December 19, 2016, now U.S. Patent 11,473,083, which claims the benefit of U.S. Provisional Application No. 62/270,165, filed December 21, 2015.
Information Disclosure Statement
Information disclosure statements filed 7/20/2022, 7/14/2023, 11/2/2023, 7/11/2024, 1/5/2026, 2/4/2026 and 6/4/2026 have been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action. In the case that only an English abstract was identified, this is indicated. A single reference was lined through as it could not be located in the instant file or the parental document.
The IDS is accompanied by the IDS size fee.
Drawings
Figure 1 is confusing as there isa Figure 1 that is not described. The description starts with Figure 1A. Secondly, the descriptions start with Figures 1C, 1E are objected to under 37 CFR 1.83(a) because they fail to show any details as described in the specification. Specifically, the text in Figure 1C is illegible. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). A proposed drawing correction or corrected drawings are required in reply to the Office action to avoid abandonment of the application. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 7 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 2. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 7 and 2 differ by semantics that are not obvious based upon the disclosure. Claim 2 and 7 are drawn to the same steps but claim 2 is directed towards treating a subject afflicted with or susceptible to tau associated disease, claim 7 to a subject in need thereof of treatment for a tau-associated disease. According to the disclosure a subject in need is one afflicted with or susceptible to a tau associated disease. Hence, the difference is not clear.
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 1-11, 20, 21 and 27-44 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a nucleic acid molecule comprising an alphavirus replicon RNA with the nucleotide sequence of SEQ ID NO:2-18 in which the U2 position of any of SEQ ID NO:2-18 is substituted with a G and wherein at least a portion of the alphavirus genome is deleted such that at least one structural protein is not encoded, 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.
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 a method of treating a tau related disorder by use of an antisense oligonucleotide.
2) Scope of the invention. The scope of the invention is extremely broad in the target of the treatment is an extremely large group of conditions. The oligonucleotide itself is quite limited wherein even the structure of the nucleobase sequence is provided for with wherein C in any of the nucleobase sequences is either cytosine or 5-methylcytosine, and wherein at least one nucleotide of the oligonucleotide has a 2'-modification, wherein at least one internucleoside linkage of the oligonucleotide is a phosphorothioate linkage. Dependent claims further limit the structure1 of the sequence.
3) Number of working examples and guidance. The specification teaches (example 1) the format of the studies wherein nucleic acid oligonucleotides were accessed in vitro and in vivo in mice. The mice studies were performed by ICV injection. In example 2, the design of the antisense oligos were described wherein
[0149] Antisense oligonucleotide steric blockers were designed to target intron-exon junctions of constitutive exons in human Tau, the invariable exons present in all isoforms. Antisense oligonucleotide steric blockers were designed to induce exon skipping, either by hybridizing to intronic branch point sequences, targeting splice sites directly, bracketing intronic and exonic sequences, exon splicing enhancers sites.
The oligonucleotides were all 18-mer 2’O-MOE designated SEQ ID NO: 1-84 wherein in Table 2 the results in vitro in Huh7 cells were demonstrated. Those considered efficacious were tested in human neuroblastoma cells and shown in Table 3 and further evaluated for IC50. Sequences that were effective were chosen to be modify with 2′-O-methoxyethyl (2′-O-MOE) modification; and mC stands for 5-methylcytosine with phosphorothioate internucleoside linkages and linkers with
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Example 6 and table 9 provide a finalizes set up of 20 mers with the following arrangement,
[0157] Antisense oligonucleotides sequences were designed to be complementary to the shortest Tau isoform, transcript variant 4, mRNA (GenBank: NM_016841.4). BLAST analyses were performed for each oligonucleotide sequence to avoid off-target hybridization. Newly designed modified chimeric antisense oligonucleotides were designed as 5-10-5 gapmers that are 20 nucleosides in length, wherein the central gap segment comprises ten 2′-deoxynucleosides and is flanked by wing segments on the 5′ direction and the 3′ direction comprising five nucleosides each with a 2′-O-MOE ribose sugar modification. The internucleoside linkages throughout each gapmer are phosphorothioate (P═S) linkages.
The following demonstrated high efficacy.
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In example 9, human tau transgenic mice were injected with oligonucleotides by intracerebroventricular (ICV). SEQ ID NO:285 was alone able to reach levels desired of inhibition of cortex and hippocampus mRNA and cortex protein. Dose dependent inhibition was shown (see figure 4) as well as sustained inhibition (see figure 5). Further studies of inhibition on monkey Cos1 green cells and human embryonic stem cells.
4) State of the art. Tau protein targeted in the instant method is encoded by MAPT gene. Tau is a microtubule associated protein that bind and stabilizes microtubules wherein a number of mutations result in disorders. A collection of disorders defined by tau deposits in the brain are known as tauopathies and include Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, some frontotemporal dementias, and chronic traumatic encephalopathy. Post-filing, Orr et al teaches the limited level of treatment, (Trends Pharmacol Sci. 2017 pages 1-19, see page 3)
Treatment of tau-related neurodegenerative syndromes is limited and largely symptomatic. Currently, there are two classes of medication approved for cognition: cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA) receptor antagonist, each demonstrating modest effects [4] (Table 1). Motor symptoms may respond to dopaminergic regimens [5], speech therapy has shown some efficacy with aphasia syndromes, and physical therapy can prove helpful in prolonging motor function. Symptoms of apathy and depression are quite common and often respond to therapy or pharmacologic intervention, including selective serotonin reuptake inhibitors [5]. There are currently no disease-modifying therapies for tauopathies, including Alzheimer's disease
5) Unpredictability of the art. Several issues with the claims which follow. Specifically, is first the large scope of targets. The conditions while related to tau are each actually etiologically unique, Orr et al (page 2),
Each clinical syndrome presents with a unique constellation of symptoms thought to represent anatomical regions of vulnerability. Patients with “prototypical” Alzheimer's disease experience an insidious pattern of forgetfulness as pathology builds in the hippocampus and entorhinal cortex.
Yet, applicants claim a single method to treat each and that is aso therapy targeting tau. Some reasons for the lack of generality in treatment is that the function and species of tau is found to be diverse and this results in a diverse array of conditions wherein our understanding of how to treat tau disorders is incomplete. It has been found that downregulating or inhibiting tau does not appear to be the full picture and in fact Samudra identifies conditions in which lack of tau could contribute to tauopathies. Other considerations are the lack of effect on downstream events that have been established (see Samudra, J Clin Invest. 2023, pages 1-11 especially, page 3).
Even to date, the ability to treat tau-based disorders has seen little success Samudra et al, (see page 1, col 2)
Despite strong evidence for a central pathologic role of tau in neurodegenerative tauopathies, recent human clinical trials of experimental tau-targeting therapies have failed to demonstrate clinical benefit, including drugs purported to interfere with pathologic aggregation, processing, and accumulation of tau (15, 16).
Different strains of tau require understanding as (Samudra, page 5, col 1)
If tau strain or aggregate structure is key to the development of a particular human disease, failure to accurately target the relevant tau strain could result in a lack of efficacy in human trials.
What complicates the issue is applicants’ results are performed in animal models. Generally, when 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.)
However, specifically when considering tauopathies, animal models available have not correlate with clinical success in humans when looking at tau therapies (Samudra et al, page 1, col 2).
Though tau therapeutics have improved pathology in nonclinical models of tauopathy, do the recent negative human clinical trial results reflect flawed nonclinical models that inadequately model human disease? Are the models potentially predictive of therapeutic effects in human disease, but not the disease(s) in which the therapies were tested? Or is the lack of human efficacy explained by problems related to drug development, such as the wrong therapeutic target, inadequate dose, or lack of target engagement? Given these challenges, is it time to rebalance the approach to development of tau therapeutics using nonclinical models and early-stage human clinical trials
Specifically, it is shown that mouse models do not develop the full disease characteristics found in human, tau expression does not mimic that in humans altering progression and compensatory effects and murine vs human structure function differs not provide the same biochemical environment nor development of tau and the blood brain barrier differs.
In consequence, nonclinical models of tauopathy have at best partially approximated human neurodegeneration — they represent models of possibly relevant disease mechanisms.
6) Undue experimentation. 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.”
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 1-11, 20, 21 and 27-44 are rejected under the judicially created doctrine of non-statutory-type double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,473,083.
A non-statutory-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claims because the examined claim is either anticipated by, or would have been obvious over, the reference claims. Although the conflicting claims are not identical, they are not patentably distinct from each other because the cited claims of the instant invention are U.S. Patent No. 11,473,083. That is, the cited claims of U.S. Patent No. 11,473,083 are the sequences used in the method of the instant claims. Specifically, the antisense oligonucleotide of claims 1-10 are exactly those used in the methods of the instant claims. The safe harbor for non-statutory double patenting only applies for applications filed as divisional applications and hence the claims are related under the non-statutory double patenting statute.
Additionally, if a patent resulting from the instant claims was issued and transferred to an assignee different from the assignee holding the U.S. Patent No. 11,473,083, then two different assignees would hold a patent to the claimed invention of U.S. Patent No. 11,473,083, and thus improperly there would be possible harassment by multiple assignees.
Claims 1-11, 20, 21 and 27-44 are provisionally rejected under the judicially created doctrine of non-statutory-type double patenting as being unpatentable over claims of U.S. serial number 19/429,138.
A non-statutory-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim is not patentably distinct from the reference claims because the examined claim is either anticipated by, or would have been obvious over, the reference claims. Although the conflicting claims are not identical, they are not patentably distinct from each other because the cited claims of the instant invention are U.S. serial number 19/429,138. That is, the cited claims of U.S. serial number 19/429,138 are the sequences used in the method of the instant claims. Although the conflicting claims are not identical, they are not patentably distinct from each other because the cited claims of the instant invention are U.S. serial number 19/429,138. That is, claims 1-4 of U.S. serial number 19/429,138 are the sequences used in the method of the instant claims. The methods of claims 5-30 are overlapping methods to those of the instant claims. While the instant claims reference SEQ ID NO:480 for the methods, SEQ ID NO:285 recited in the copending claims is variant of this sequence and claimed in dependent claims in the instant claims. The safe harbor for non-statutory double patenting only applies for applications filed as divisional applications and hence the claims are related under the non-statutory double patenting statute.
Additionally, if a patent resulting from the instant claims was issued and transferred to an assignee different from the assignee holding the U.S. serial number 19/429,138, then two different assignees would hold a patent to the claimed invention of U.S. serial number 19/429,138, 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
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/MARIA MARVICH/ Primary Examiner, Art Unit 1633
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