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 .
Election/Restrictions
Applicants’ election with traverse of Group I (claims 1-21) in the reply filed on May 20, 2026 is acknowledged. The traversal is on the ground that the groups share the same prior art search space, the same specification, and fall within the area of expertise. This is not found persuasive because the therapeutic double-stranded RNA (tdsRNA) can allegedly be used for a variety of purposes, including treatment of any of the vast number of neuroinflammation diseases, disorders, and conditions. Thus, searches for the compositions comprising the tdsRNA can range from a wide variety of diseases and conditions. Because the searches are significantly different for the claimed treatment of neuroinflammation are different from the searches of the other potential treatments for a wide variety of diseases and conditions, the restriction is maintained.
In addition, Applicants’ election of the species of neuroinflammation disorder syndrome, Alzheimer’s disease, and cognitive function decline is also deemed proper. As noted above, the elected species are again deemed to be widely variant and the searches for one species is not the same as a search for the other species. And the diseases and conditions to be treated are not necessarily related and the searches are not deemed to be coextensive.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-21 read on the elected species and are therefore under examination.
Information Disclosure Statement
The Information Disclosure Statements filed November 1, 2023 and May 14, 2024 have been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of the terms TRITON® at page 23, line 24; TWEEN® at page 23, line 24; SUPERASE® at page 27, line 19; RNASOUT® at page 27, line 19; CAPMUL® at page 29, line 3; ESTERAM® at page 29, line 4; MIGLYOL® at page 29, line 4; ASTELIN® at page 37, line 25; PATANASE® at page 37, line 26; APTAR PHARMA® at page 36, lines 26-27; VIANASE® at page 37, line 27; ZETONNA® at page 37, line 28; OPTINOSE® at page 37, line 20; LUER LOK® at page 38, line 11; ULTRAVENT® at page 29, line 9; VENTOLIN® at page 39, line 10; and SPINHALER® at page 39, line 11; which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities:
At claim 1, line 6, “and” should be inserted after “(formula 1);”.
Appropriate correction is required.
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 1-21 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1 the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are broadly drawn to a method for treating, reducing or preventing neuroinflammation in a subject comprising administering a composition comprising a therapeutically effective amount of a therapeutic double stranded RNA (tdsRNA), with the tdsRNA is at least one selected from at least one of rIn·r(CxU)n (formula 1) or rugged dsRNA (formula 5).
The state of the art, the unpredictability of the art, and the relative skill of the ordinary artisan
It is well established in the art that administration of a therapeutics are able to treat neuroinflammation or and reduce the symptoms of that disease in a subject. For example, Lee et al. (10 Biomedicines 2518, 1-14 (2022)) disclose stress-related neuroinflammation can be treated with N-methyl-D-aspartate (NMDA) receptor antagonists, peroxisome proliferator-activated receptor agonists, and angiotensin-converting enzyme inhibitors can improve neuroinflammation (abstract). However, the prevention of neuroinflammation disorders by administration of a pharmaceutical composition comprising any therapeutic, including the claimed therapeutic double stranded RNAs (tdsRNAs) is unpredictable. Further, mere administration of such a therapeutic at best ameliorates some of the symptoms or progression of an infection, and will not prevent a neuroinflammation disease, condition, or disorder. In addition, the skill of those in the relative art is high, but still, given the state and unpredictability of the art, undue experimentation would be required to determine if any neuroinflammation disease, disorder, or condition is prevented, or rather than just treated by administration of any pharmaceutical composition. Prevention of a neuroinflammation disorder, disease, or condition cannot be predictably accomplished, much less via the administration of a pharmaceutical composition comprising the tdsRNA.
Further, It is also known in the art that Alzheimer’s disease affects millions of people. See Alzheimer’s Association Report (9 Alzheimer’s & Dementia 208-245 (2013)). According to the Alzheimer’s Association Report, Alzheimer’s disease has a large impact on public health, and that the number of people with Alzheimer’s disease is expected to grow as the population ages (abstract and Figure 4). The Alzheimer’s Report provides an overview of Alzheimer’s disease, its symptoms, diagnosis, and stages (Section 2, Overview of Alzheimer’s disease). The Alzheimer’s Report further provides information regarding the costs of Alzheimer’s disease, including health care, long-term care, and hospice care (Section 6, Use and costs of health care, long term care, and hospice). The Alzheimer’s Report notes, while a variety of drugs and therapies are being investigated, “[n]one of the treatments available today for AD slows or stops the death and malfunction of neurons in the grain that cause AD symptoms and make the disease fatal.” (page 214, column 2, second and third full paragraphs).
Tani (25 International Journal of Molecular Sciences 12284, 1-32 (2024)) discloses that RNA therapeutics have undergone remarkable evolution and offer new possibilities for treating previously intractable diseases (abstract). Tani discloses that RNA therapeutics include antisense oligonucleotides (ASOs), small interfering RNas (siRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) (abstract). Tani discloses, however, that significant challenges remain, including stability issues, delivery to target tissues, potential off-target effects, and immunogenicity concerns (abstract). Tani discloses the challenges of RNA therapeutics and potential strategies to overcome them (Table 4). Tani discloses the three significant challenges to address with regard to RNA therapeutics (page 28, first full paragraph). Tani discloses that delivery systems for delivering RNA drugs to specific cells and tissues, noting that because RNA molecules are relatively large and charged, it is difficult for them to pass through cell membranes and reach target tissues unaided (page 28, first full paragraph). Tani disclose that RNA stability is a second challenge because RNA is inherently unstable and rapidly degraded by RNA-degrading enzymes in the body (page 28, first full paragraph). Tani discloses that “off-target effects” are an additional challenge, or the phenomenon of affecting regions or genes other than the intended target (page 28, first full paragraph). Although Tani does disclose potential methods of addressing these challenges, additional experimentation is necessary to provide RNA therapeutics, such as the instantly claimed tdsRNA.
Hampel et al. (95 Progress in Neurobiology 718-728 (2011)) also discuss Alzheimer’s disease and discloses that there is an enormous burden put upon individuals, families, caregivers, and society itself (abstract). Hampel discloses provides an overview on available therapeutic approaches, and notes that “[t]hese still unmet needs call for ever more concerted and focused efforts in research across the world to combat the erupting and as yet uncontrolled epidemic of AD” (abstract). In particular, Hampel discloses that Alzheimer’s disease has changing and fluctuating symptoms that can last for years, and thus, treatment efficacy is difficult to determine (page 724, column 1, second, third, and fourth full paragraphs). Hampel discloses that a single standard Alzheimer’s disease treatment type (acetylcholine esterase inhibitors) are used for mild to moderate Alzheimer’s disease patients, and are “of modest efficacy” and that it is not possible to identify patients that will respond favorably to such treatment (page 724, paragraph bridging columns 1 and 2).
Brunet de Courssou et al. (145 Brain 816-831 (2022)) disclose the use of antisense (AOS) and RNA therapies in neurological diseases, which show promise, but with many unknowns still in play, citing failure of treatment of Huntington’s disease or due to long-term pre-clinical toxicity in multiple system atrophy and cystic fibrosis (abstract). Brunet de Courssou discloses that short- and long-term safety issues are currently under discussion, with a knowledge gap regarding the long-term efficacy and toxicity of new emerging treatments (page 827, column 2, final paragraph). Brunet de Courssou also discloses that even apart from technical, safety, and scientific aspects, cost-effectiveness studies will be required in order to address potential unaffordability for these treatments (page 827, column 2, final paragraph).
Thus, there is presently no way of predicting which therapies would be useful for the amelioration of neurodegeneration and/or recent memory loss, and whether these therapies include tdsRNAs. Nor is it predictable which Alzheimer’s patients will respond favorably, or unfavorably, to any given treatment. As such, the claimed tdsRNAs would not predictably be useful for the amelioration of neurodegeneration and/or recent memory loss associated with Alzheimer’s disease or any other neuroinflammation disease, disorder, or condition.
Amount of experimentation required and the direction or guidance presented
In order to determine how to act, one of ordinary skill in the art would have to practice undue experimentation to determine if a neuroinflammation disease, condition, or disorder would be treatable by a pharmaceutical composition comprising the claimed tdsRNAs. While neuroinflammation disease, disorders, or conditions can be treated or symptoms ameliorated, such diseases, conditions, and disorders thereof cannot necessarily be prevented. Even if an effective therapeutic pharmaceutical composition comprising the claimed tdsRNA was identified and administered to a subject, the result would be just that: treatment of a neuroinflammation disease, conditions, or disorder in a subject. The ability to administer an composition to a subject having any neuroinflammation disorder, disease, or condition, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, postoperative cognitive dysfunction, spinal cord injury, or any other neuroinflammation disease, condition, or disorder is not representative of the ability to predictably make and use the invention. In addition, the specification, as filed, fails to provide any particular direction or guidance which resolves the known unpredictability in the art associated with preventing any neuroinflammation disease, condition, or disorder in a subject.
In addition, in order to determine which of the tdsRNAs encompassed by the claims, one of ordinary skill in the art would have to practice undue experimentation to determine which Alzheimer’s patients (or any neuroinflammation patient) would benefit from treatment with a tdsRNA. The isolation and characterization of the single tdsRNA is not representative of the ability to predictably make and use the invention. In addition, the specification, as filed, fails to provide any particular direction or guidance which resolves the known unpredictability in the art associated with determining which treatments would ameliorate neurodegeneration and/or recent memory loss in any given Alzheimer’s patient. Given the wide range of symptoms and neuroinflammation diseases, conditions, and disorders, the vast fluctuations and progressions of Alzheimer’s in any given patient, treating the neurodegeneration and/or recent memory loss in an Alzheimer’s patient with any tdsRNA is simply not predictable.
Nature of the invention, the presence or absence of working examples, and the breadth of the claims
Although the specification does disclose administration of tdsRNAs to Alzheimer’s patients, only one tdsRNA was studied (poly I:polyC12U) was studied, and only in Alzheimer’s patients. Extrapolation of the single tdsRNA and the single disease to any other tdsRNA and/or neuroinflammation disease, condition or disorder is simply unpredictable and would require undue experimentation. Thus, the specification fails to disclose how to prevent any neuroinflammation disease, disorder, or condition, as encompassed by the claims. The invention requires that a neuroinflammation disease, disorder, or condition be prevented by the administration of a pharmaceutical composition comprising the claimed tdsRNAs, rather than treated so as to ameliorate or reduce any disease symptoms. The invention the specification does not provide any disclosure to enable the claims.
In view of the lack of the predictability of the art to which the invention pertains, undue experimentation would be required to make and use the claimed invention to prevent neuroinflammation diseases, disorders, and/or conditions in a subject with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the method based on administration of pharmaceutical composition comprising tdsRNAs to prevent neuroinflammation diseases, according to the invention, and absent working examples that provide evidence that is reasonably predictive of the ability of preventing the neuroinflammation disease, disorder, and/or condition by the administration of a pharmaceutical composition comprising the claimed tdsRNA the claims are not enabled. Further, undue experimentation would be required to make and use a tdsRNA to ameliorate neurodegeneration and recent memory loss in Alzheimer’s disease patients and/or any other neuroinflammation disease, condition, or disorder according to the claimed invention with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the claimed tdsRNA to ameliorate neurodegeneration and recent memory loss in Alzheimer’s disease patients, and absent working examples that provide evidence that is reasonably predictive of the ability of any tdsRNA to ameliorate any neuroinflammation disease, disorder, or condition, the claims are not enabled.
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 1-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
At claim 1, lines 5-7, it is not clear if the therapeutic double stranded RNA (tdsRNA) can have one strand of “(formula 1)” in combination with rugged dsRNA, since the rugged ds RNA (formula 5) is already a double stranded RNA. If the claim means that both strands of the tdsRNA are of rIn·r(CxU)n (formula 1) or that the tdsRNA is rugged dsRNA (formula 5), it is suggested that “at least one” at line 5 be deleted.
Claims 2-21 depend from claim 1, and are therefore included in this rejection.
At claim 13, it is not clear how the tdsRNA RNA comprises both rIn·ribo(C11-14U)n and rugged dsRNA, since rugged dsRNA is already a double stranded RNA.
Claim 14 recites the limitation "the uracil base" in line 6. There is insufficient antecedent basis for this limitation in the claim.
Claim 17 recites the limitation "the uracil base" in line 8. There is insufficient antecedent basis for this limitation in the claim.
Claim 14 recites the limitation "the cytosine base" in line 9. There is insufficient antecedent basis for this limitation in the claim.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Carter et al. (U.S. Patent No. 8,722,874, issued May 13, 2014) disclose a rugged double stranded RNA (dsRNA) that binds with high specificity to toll-like receptor 3 (TLR3) (abstract). Carter discloses that the rugged dsRNA has the structure of (poly I, poly C30,U) (abstract). However, Carter does not disclose treatment of neuroinflammation diseases, disorders, and conditions.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, NEIL HAMMELL can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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