DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant's correspondence and preliminary amendment filed on June 12, 2024 is acknowledged. Claims 1-35 are canceled; claims 36-54 are new. Claims 36-54 are pending and presently subject to examination.
Information Disclosure Statement
3. 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.
The references should be placed on an information disclosure statement if Applicant would like them considered.
Objection to the Specification
4. The instant specification is objected to for the following reasons:
There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “MDS” at pg. 14, ln. 16), which is a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology whenever possible; furthermore the terms should be capitalized wherever it appears 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. Please, review the specification for other improper trademarks and correction is required.
Claim Rejections - 35 USC § 112
5. 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.
Written Description
6. Claims 36-54 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 claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
No Written Description for the Breath of the Claims: a method for a sex-specific treating or inhibiting of the development of a disease or disorder associated with an aberrant functionality of activity-dependent neuroprotective protein (ADNP); wherein the disease is selected from tauopathy, neurodegenerative disease, neurodevelopmental disease and mental disease (i.e., claim 37); or wherein the disease or disorder is selected from PSP, schizophrenia, aMCI, Alzheimer’s disease, ADNP syndrome, autism and muscle disease (e.g., claim 38)
Claims 36-49 are directed to a method for a sex-specific treating or inhibiting of the development of a disease or disorder associated with aberrant functionality of activity-dependent neuroprotective protein (ADNP). The claims further recite various diseases, such as tauopathy, neurodegenerative disease, neurodevelopmental disease and mental disease (i.e., claim 37); progressive supranuclear palsy (PSP i.e., claim 39); schizophrenia (i.e., claim 41); amnestic mild cognitive impairment (aMCI; i.e., claim 44); and Alzheimer’s disease (i.e., claim 45). The claims therefore broadly encompass treating or inhibiting any disease or disorder “associated with” aberrant functionality of ADNP (parent molecule of NAP peptide), including the select neurological diseases or disorders explicitly recited in the claims, by administering NAP. However, an “association” between the activity of a protein and a disease is not the same as a causal relationship. Therefore, it is not apparent that Applicant has possession of treating or inhibiting any disease at all.
The specification only discloses: (i) a statistical reanalysis of clinical trial NCT01110702 (which originally concluded NAP was not effective for treating PSP) at Example 1; (ii) a correlation between ADNP truncation expression levels with e.g., Alzheimer’s disease at Example 2; (iii) a statistical reanalysis of an aMCI clinical trial at Example 3; and (iv) a statistical reanalysis of a schizophrenia clinical trial at Example 4.
FIG. 4 shows statistically insignificant effects on phosphorylated tau in the females treated with NAP. FIG. 8 shows a statistically significant effect of NAP on Geriatric Depression Score (GDS) score in females at 52 weeks compared to placebo, but not in males. Similar results are shown for the other clinical trials, however only one cherry picked metric is shown for each of aMCI and schizophrenia; and none are shown for Alzheimer’s disease, or any other neurological disease.
The claims require that the diseases be “associated with” aberrant ADNP functionality. However, an “association” or correlation between the activity of a protein and a disease does not mean that the disease is caused by the protein’s functionality, and furthermore treatable via the protein’s signaling pathway. Therefore, it is unclear if any of the diseases or disorders encompassed by the claims are treatable by NAP based on possible associations with aberrant ADNP functionality. To address this issue, a brief assessment of the state of the art of ADNP’s signaling pathway and the difference between correlation and causality in biomedical contexts is made herein, which shows that it is very unpredictable whether a protein’s aberrant activity, correlating to a disease or disorder, also indicates the disease or disorder is caused by the aberrant activity and furthermore treatable via that protein’s signaling pathway.
Gozes ("ADNP regulates cognition: a multitasking protein." Frontiers in Neuroscience 12 (2018): 873) is an opinion discussing ADNP’s association with cognition (see the abstract). Gozes shows at Figure 1 that ADNP is involved in diverse signaling networks, ranging from interactions with transcription factors to microtubule-associated protein. Therefore, since ADNP interacts with such a diverse array of proteins, aberrant ADNP functionality is expected to be associated with diverse causes and diseases, but not necessarily causally related to any of them. Gozes Figure 1 is reproduced below for Applicant’s convenience:
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Smith et al. ("Mendelian randomization: genetic variants as instruments for strengthening causal inference in observational studies." Biosocial surveys. National Academies Press (US), 2008) is a book chapter discussing causal inference in biomedical contexts, and is presented herein to expound on the distinction between correlation and causation. Smith et al. teaches: “conventional observational study designs have yielded findings that have failed to be confirmed by randomized controlled trials. Observational studies demonstrated that beta carotene intake was associated with a lower risk of lung cancer mortality, and this stimulated an already active market for vitamin supplements that was based on the notion that they substantially influence chronic disease risk. The scientists involved in conducting the observational studies advocated taking supplements in material intended for the public and also, relying on observational data, concluded ‘Available data thus strongly support the hypothesis that dietary carotenoids reduce the risk of lung cancer.’ However large-scale randomized controlled trials reported disappointing findings: beta carotene supplementation produced no reduction in risk of lung cancer.” Smith et al. at pg. 337, first paragraph. Smith et al. gives further examples of how hopeful associations between e.g., a biomarker and a disease (for example, CRP and heart disease), do not translate into successful treatment of the disease because the biomarker is not causally related to the disease. Smith et al. at pg. 348, first paragraph.
Therefore, without actually performing the required experiments, it is unpredictable how NAP may treat or inhibit the development of the disease or disorders associated with an aberrant functionality of ADNP encompassed by the claims. For example, the clinical trial reanalyzed by Applicant concluded that ADNP was not effective for the treatment of PSP. Applicant has not performed the required additional experiments to substantiate that any subject population may beneficially be treated by NAP. Neither the art nor the specification provides a sufficient representative number of examples to meet the written description requirement for instant claims directed to treating any disease associated with aberrant ADNP functionality. It is therefore unknown how the instantly claimed NAP treatments would treat any of the encompassed diseases. Applicant has not shown possession of successfully treating any disease or disorder associated with aberrant ADNP functionality.
No Written Description for the Breath of the Claims: “a method for a sex-specific treating or inhibiting of the development of a disease or disorder”
Claims 36-49 are directed to a method for a sex-specific treating or inhibiting of the development of a disease or disorder associated with aberrant functionality of activity-dependent neuroprotective protein (ADNP). The claims further recite various doses of NAP for treating male vs female patients. The claims therefore broadly encompass treating any disease associated with aberrant functionality of ADNP by administering NAP based on the sex of the patient. However, the specification does not disclose any differential administration of NAP to treat any diseases based on the sex of a patient.
The specification only discloses regarding alleged sex-specific effects: (i) a statistical reanalysis of clinical trial NCT01110702 (which originally concluded NAP was not effective for treating PSP) at Example 1; (ii) a statistical reanalysis of an aMCI clinical trial at Example 3; (iii) a statistical reanalysis of a schizophrenia clinical trial at Example 4; and (iv) a demonstration of sex-specific expression of hace1, associated with Alzheimer’s disease, by NAP administration in ADNP transgenic mice at Example 5.
Select metrics of the clinical trials are reanalyzed in an attempt to ascertain male vs female specific effects. For example, FIG. 5 shows a correlation matrix for the PSP clinical trial between: age, ventricular volume, SEADL score, and PSPPRS score—of the six comparisons, ventricular volume comparisons were the most statistically significant to suggest a sex-specific effect in females of the NAP treatment, and more statistically significant than comparisons between the disease progression scores. However, a method of sex-specific inhibition of ventricular volume enlargement is not instantly claimed.
FIG. 4 shows statistically insignificant effects of phosphorylated tau in the females treated with NAP. FIG. 8 shows a statistically significant effect of NAP on Geriatric Depression Score (GDS) score in females at 52 weeks compared to placebo, and not males—however the females are not compared to the males. A comparison between the females and males would likely show no difference between the NAP treated male and female GDS endpoints, but a significant difference between the placebo male and female GDS endpoints. This demonstrated difference between placebo groups is not encompassed by the claims. Similar results are shown for the other clinical trials, suggesting a possible difference in the efficacy of NAP for select metrics of aMCI (i.e., DMTS CBL score) and schizophrenia (i.e., UPSA score), however the males are never compared to the females statistically to firmly establish the difference. Only one cherry picked metric is shown for each of aMCI and schizophrenia; none are shown for Alzheimer’s disease, or any other neurological disease.
The claims require that the diseases be treated, inhibited, or prevented in a sex-specific manner. The instant specification has only demonstrated: limited sex-specific effects on select metrics associated with PSP, aMCI, and schizophrenia. A full study exploring the extent of the sex-specific effects for any of the diseases is not disclosed because: the present disclosure is derived from clinical trials that were not focused on sex-specific effects. Therefore, the presented metrics are far too limited to establish possession of any of the claim-recited diseases. For example, the strongest evidence provided regarding the effects of NAP in PSP is that on sex-specific ventricular volume differences. Said ventricular volume differences are measurements of brain atrophy caused by PSP—an indirect measurement of disease progression that is not specific to PSP. To address this issue, a brief assessment of the state of the art of ventricular volume as it relates to PSP is provided below, which shows that it is very unpredictable how changes in ventricular volume relate to effective treatment of PSP.
Quattrone et al. ("Brain atrophy does not predict clinical progression in progressive supranuclear palsy." Movement Disorders 40.11 (2025): 2517-2530) is brief report directed to endpoint measurements in PSP clinical trials (see the abstract at background). Quattrone et al. concludes: “[b]aseline clinical severity and brain atrophy could not predict individual clinical progression, suggesting no need for MRI-based stratification of patients in future PSP trials.” Since ventricular volume enlargement is synonymous with brain atrophy, the cited reference shows that instant disclosure of sex-specific effects of NAP on ventricular volume in PSP context have no bearing on the clinical progression of the disease, and thus sex-specific treatment of PSP as instantly claimed.
Therefore, without actually performing the required experiments, it is unpredictable how NAP may sex-specifically treat any of the claim-recited diseases. Neither the art nor the specification provides a sufficient representative number of examples to meet the written description requirement for instant claims directed to sex-specific disease treatment subject matter. It is therefore unknown how the instantly claimed NAP treatments would treat female versus male sex-specifically for the claim-recited diseases. Applicant has not shown possession of treating any disease in a sex-specific manner.
No Written Description for the Breath of the Claims: “preventing the development of PSP” (claim 40); “prevention of Alzheimer’s disease” (claim 45); “preventing side effects of an anti-amyloid-β therapy” (claim 50).
The indicated claims recite that PSP, Alzheimer’s disease, or side effects of anti-amyloid-β therapy are “prevented.” The claims therefore encompass the complete prevention of these diseases and side effects.
The Specification teaches nothing about treating side effects of an anti-amyloid-β therapy, treating Alzheimer’s disease, and the information regarding alleged treatment benefits of NAP for PSP originated from a clinical trial that concluded there was no therapeutic benefit, let alone an ability to prevent PSP. The specification fails to demonstrate Applicant’s possession of prevention of any of the claim-recited disorders or side effects. To address the issue of the term “prevention” recited in the claims, the dictionary definition of the term is presented herein, which shows that “prevention” means the complete prevention of the occurrence of the thing.
The Meriam-Webster dictionary’s first definition of the term “preventing” is “to keep from happening or existing,” and the dictionary provides the example of taking steps to prevent a war from starting.
Such prevention was not demonstrated in the specification, nor known in the art, with regards to any of the claim-recited indications.
Neither the art nor the specification provides a sufficient representative number of methods for of preventing side effects of an anti-amyloid-β therapy, or preventing PSP or Alzheimer’s disease with NAP, to meet the written description requirement for instant claims directed to said subject matter.
It is therefore unknown how NAP would prevent side effects of an anti-amyloid-β therapy, or prevent PSP and Alzheimer’s disease. Applicant has not shown possession of a single species of the invention that has the claimed function(s). The specification therefore provides insufficient written description to support the instantly claimed “preventing” subject matter.
No Written Description for the Breath of the Claims: “a method for ameliorating and/or preventing side effects of an anti-amyloid-β therapy in a subject in need thereof” (i.e., claims 50-54)
Claims 50-54 are further directed to a method of ameliorating and/or preventing side effects of an anti-amyloid-β therapy in a subject in need thereof by administering NAP.
The specification discloses at the end of Example 1 that the FDA-approved Alzheimer’s drug aducanumab (an anti-amyloid-β therapy) results in dose-dependent ventricle enlargement, and speculates that NAP may beneficially treat said side effect. The specification’s findings with regard to NAP and ventricle enlargement in PSP context are discussed above. The claims require ameliorating and/or preventing side effects of an anti-amyloid-β therapy; however, no examples showing NAP to ameliorate and/or prevent side effects (i.e., ventricular enlargement) of an anti-amyloid-β therapy are disclosed in the instant specification. To address this issue, a brief assessment of the state of the art of amelioration and/or preventing the side-effects of anti-amyloid-β therapy is presented below, which shows the cause of this side effect is unknown, and therefore it is unknown how NAP may ameliorate and/or prevent said side effects.
Burling ("Why Do the Brains of Patients Treated With Anti-Amyloid Agents Shrink Faster?: Alzheimer's Disease Experts Address the Mystery." Neurology Today 25.2 (2025): 28) is a discussion with Alzheimer’s disease experts on the side effects of anti-amyloid-β therapy. Dr. Wolk comments on the cause of the side effects: “The short answer is we don't know.” The cited reference therefore demonstrates it is unknown in the art what effect NAP may have on the mysterious side effects of anti-amyloid-β therapy.
Neither the art nor the specification provides a sufficient representative number of methods for of ameliorating and/or preventing side effects of an anti-amyloid-β therapy, let alone with NAP, to meet the written description requirement for instant claims directed to said subject matter.
It is therefore unknown how NAP would ameliorate and/or prevent side effects of an anti-amyloid-β therapy. Applicant has not shown possession of a single species of the invention that has the claimed function(s). The specification therefore provides insufficient written description to support the instantly claimed ameliorating and/or preventing side effects of an anti-amyloid-β therapy in a subject in need thereof by administering NAP subject matter.
Given all of the above, the cited reference therefore demonstrate that Applicant is not in possession of: any of the instantly claimed subject matter.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
7. Claims 36-54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for methods for a sex-specific treating or inhibiting of the development of a disease or disorder by administering NAP; or methods for ameliorating and/or preventing side effects of an anti-amyloid-β therapy by administering NAP. 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.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claims:
The claims are drawn to methods for a sex-specific treating or inhibiting or preventing of the development of a disease or disorder associated with aberrant ADNP functionality by administering NAP; and methods for ameliorating and/or preventing side effects of an anti-amyloid-β therapy by administering NAP. The dependent claims further specify the disease (e.g., neurodegenerative disease, Alzheimer’s, schizophrenia, PSP, aMCI) and, doses of the NAP for administering to male or female, and that PSP and Alzheimer’s disease may be prevented with NAP. The claims are therefore broad and encompass sex-specific treatment of any disease or disorder associated with aberrant ADNP functionality, and ameliorating and/or preventing side effects of an anti-amyloid-β therapy with large dose ranges of NAP.
(5) The predictability or unpredictability of the art:
The state of the art indicates it is very unpredictable how well NAP will work for sex-specific treating, preventing, or inhibiting of the development of a disease or disorder; or ameliorating and/or preventing side effects of an anti-amyloid-β therapy; or preventing PSP and Alzheimer’s disease.
Regarding sex-specific treating or inhibiting of the development of a disease or disorder, the instant specification discusses in depth the effects of NAP on ventricular volume in PSP patients in Example 1 and shows in FIG. 5 the most significant sex-specific PSP NAP effects on SEADL and PSPRS scores when correlated to ventricular volume (i.e., significantly greater than correlating the SEADL and PSPRS scores to each other). However, the ventricular volume effects are not equivalent to treating a neurological disease, let alone PSP, as evidenced by Quattrone et al:
Quattrone et al. is brief report directed to endpoint measurements in PSP clinical trials (see the abstract at background). Quattrone et al. concludes: “[b]aseline clinical severity and brain atrophy could not predict individual clinical progression, suggesting no need for MRI-based stratification of patients in future PSP trials.” Since ventricular volume is synonymous with brain atrophy, the cited reference demonstrates it is very unpredictable what relevance, if any, ventricular volume has on treatment of e.g., PSP.
Regarding ameliorating and/or preventing side effects of an anti-amyloid-β therapy by administering NAP, the it is very unpredictable what effect will have on said side effects since the cause of the side effects are unknow.
For example, Burling ("Why Do the Brains of Patients Treated With Anti-Amyloid Agents Shrink Faster?: Alzheimer's Disease Experts Address the Mystery." Neurology Today 25.2 (2025): 28) is a discussion with Alzheimer’s disease experts on the side effects of anti-amyloid-β therapy. Dr. Wolk comments on the cause of the side effects: “The short answer is we don't know.” The cited reference therefore demonstrates it is unknown in the art what effect NAP may have on the mysterious side effects of anti-amyloid-β therapy.
Regarding “preventing the development of PSP” (claim 40); “prevention of Alzheimer’s disease” (claim 45); and “preventing side effects of an anti-amyloid-β therapy” (claim 50), it is very unpredictable if the claim-recited indications can be “prevented” by NAP, let alone if it is possible with any therapeutic.
The Meriam-Webster dictionary’s first definition of the term “preventing” is “to keep from happening or existing.” The claims therefore encompass the complete prevention of these diseases and side effects. Such was not demonstrated in the specification, nor known in the art, with regards to any of the claim-recited indications.
The Specification teaches nothing about treating side effects of an anti-amyloid-β therapy, treating Alzheimer’s disease, and the information regarding alleged treatment benefits of NAP for PSP originated from a clinical trial that concluded there was no therapeutic benefit, let alone an ability to prevent PSP.
It is therefore wholly unpredictable how NAP would prevent side effects of an anti-amyloid-β therapy, or prevent PSP and Alzheimer’s disease. Applicant has not demonstrated a single species of the invention that has the claimed function(s).
Therefore, without actually performing the required experiments, it is very unpredictable which members of the genus of neurological diseases instantly claimed can be treated with NAP is a sex-specific manner, if at all, or if NAP will have any benefit at all for ameliorating and/or preventing side effects of an anti-amyloid-β therapy.
6) the amount of direction or guidance provided by the inventor:
The specification only discloses: (i) a statistical reanalysis of clinical trial NCT01110702 (which originally concluded NAP was not effective for treating PSP) at Example 1; (ii) a correlation between ADNP (parent molecule of NAP peptide) and ADNP truncation expression levels with e.g., Alzheimer’s disease at Example 2; (iii) a statistical reanalysis of an aMCI clinical trial at Example 3; (iv) a statistical reanalysis of a schizophrenia clinical trial at Example 4; and (v) a demonstration of sex-specific expression of hace1, associated with Alzheimer’s disease, by NAP administration in ADNP transgenic mice at Example 5.
Select metrics of the clinical trials are reanalyzed to ascertain male vs female specific effects. For example, FIG. 5 shows correlation plots for the PSP clinical trial of: age, ventricular volume, SEADL score, and PSPPRS score—of the six comparisons, ventricular volume comparisons were the most statistically significant to suggest a sex-specific effect in females of the NAP treatment, and more statistically significant than comparisons between the disease progression scores. However, a method of sex-specific reduction of ventricular volume enlargement is not instantly claimed.
FIG. 4 shows statistically insignificant effects of phosphorylated tau in the females. FIG. 8 shows a statistically significant effect of NAP on Geriatric Depression Score (GDS) score in females at 52 weeks compared to placebo, and not males—however the females are not compared to the males. A comparison between the females and males would likely show no difference between the NAP treated male and female GDS endpoints, but a significant difference between the placebo male and female GDS endpoints. This demonstrated difference between placebo groups is not encompassed by the claims. Similar results are shown for the other clinical trials, suggesting a possible difference in the efficacy of NAP for select metrics of aMCI (i.e., DMTS CBL score) and schizophrenia (i.e., UPSA score), however the males are never compared to the females statistically to firmly establish the difference. Only one cherry picked metric is shown for each of aMCI and schizophrenia; none are shown for Alzheimer’s disease, or any other neurological disease.
Regarding ameliorating and/or preventing side effects of an anti-amyloid-β therapy by administering NAP, the specification discloses at the end of Example 1 that the FDA-approved Alzheimer’s drug aducanumab (an anti-amyloid-β therapy) results in dose-dependent ventricle enlargement, and speculates that NAP may beneficially treat said side effect.
Given the evidence above, one of skill in the art could not reasonably extrapolate the instant findings primarily regarding NAP’s effect on ventricular volume to the breadth of the claimed methods. It would be undue experimentation to determine which of the instantly claimed neurological diseases indeed exhibit a sex-specific response to NAP (and the doses for achieving the sex-specific effect, or if NAP could ameliorate and/or prevent side effects of an anti-amyloid-β therapy at all.
8) the quantity of experimentation needed to make or use the invention:
It would be undue experimentation to make or use the invention encompassed by the breadth of the claims because: (i) each of the claim-recited neurological disease would have to be tested with NAP in a sex-specific manner; and (i) NAP would need to be tested with anti-amyloid-β therapy. Applicant has not done any of the required work to enable the instantly claimed-invention but instead performed data analysis on studies not designed to examine the possibilities of sex-specific effects of NAP. It is also pure speculation that NAP would ameliorate and/or prevent the side effects associated with anti-amyloid-β therapy.
In conclusion, the claimed invention does not provide enablement for any of the instantly claimed subject matter. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
8. 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 36-49 and 52 are rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
A. Claim 36 recites that disease or disorder is “associated with” an aberrant functionality of ADNP. The term “associated with” is not defined in the specification; it is unclear if “associated with” means the aberrant functionality of ADNP is a requirement of the disease. Are any diseases other than those recited in the claims “associated with” aberrant ADNP functionality, or do the claims exclude the claim-recited diseases if the subject has normal ADNP functionality? It is unclear as to how the disease or disorder is can be “associated with” an aberrant ADNP functionality because either the aberrant ADNP functionality is causal to the disease or it is not. Also, what aberrant functionalities of ADNP are encompassed by the “association with” the diseases and disorders? Appropriate clarification and/or correction is requested.
B. Claim 40 depends from claim 39 and recites the term “the treating or preventing.” There is insufficient antecedent basis for the limitation “preventing” in the claim because claim 39 recites “the method comprises treating or inhibiting the development [of PSP.]” Appropriate clarification and/or correction is requested.
C. Claims 40 recites the term “characterized in,” and claims 46, and 52 recite the term “characterized by.” It is unclear if any of the features that follow the term “characterized in” or “characterized by” are required features of the methods. For example, if the method of claim 46 is characterized by the subject is at the prodromal stage of the disease, is it required that the subject is at the prodromal stage of the disease? Appropriate clarification and/or correction is requested.
Claim Rejections - 35 USC § 102
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
10. Claims 36-38, 45, and 48-49 are rejected under 35 U.S.C 102 (a)(1) as anticipated by Sragovich et al. ("ADNP plays a key role in autophagy: from autism to schizophrenia and Alzheimer's disease." Bioessays 39.11 (2017): 1700054) in light of Javitt et al. ("Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia." Schizophrenia research 136.1-3 (2012): 25-31).
Claim 36 is directed to a method for a sex-specific treating or inhibiting of the development of a disease or disorder associated with an aberrant functionality of activity-dependent neuroprotective protein (ADNP) in a subject in need thereof comprising administering to said subject a peptide comprising the amino acid sequence NAPVSIPQ (SEQ ID NO: 1; NAP peptide) and a pharmaceutically acceptable carrier.
Claim 37 is directed to the method according to claim 36, wherein the disease or disorder is selected from a tauopathy, neurodegenerative disease, neurodevelopmental disease and mental disease.
Claim 38 is directed to the method according to claim 36, wherein the disease or disorder is selected from progressive supranuclear palsy (PSP), schizophrenia, amnestic mild cognitive impairment (aMCI), Alzheimer's disease, ADNP syndrome, autism and muscle disease.
Claim 45 is directed to the method according to claim 38, wherein the method comprises sex-specific treatment or prevention of Alzheimer's disease.
Claim 48 is directed to the method according to claim 36, comprising intranasal administration of the peptide.
Claim 49 is directed to the method according to claim 36, comprising inhibiting neurodegeneration in the subject.
Sragovich et al. is directed to the role of ADNP in schizophrenia and Alzheimer’s disease (see the title). Sragovich et al. concludes: “NAP presents a different approach on top of traditional schizophrenia treatments (antipsychotics), which act through D2 receptors blockade, and produce a high rate of extrapyramidal symptoms as side effects. Based on the known link between the autophagy and microtubule systems, NAP, being a short 8-amino-acid peptide, presents several advantages including brain bioavailability and ease of use (intranasal administration). A brief overview of the ADNP/NAP autophagy interaction is given in Figure 1. Importantly, NAP was previously shown to have a safe clinical profile in several cohorts, protecting cognition in patients suffering from AD-preceding amnestic MCI, as well as enhancing daily functions in schizophrenia patients [citing Javitt et al]. Therefore, NAP may be considered as a novel therapeutic approach specifically for schizophrenia treatment, as well as other neuropsychiatric, neurodegenerative and neurodevelopmental disorders. In addition, given the sexual divergent nature of ADNP, as previously observed in our ADNP-deficient mouse model, and the great significance of gender differences when treating patients, future studies must take into consideration this important aspect when being designed.”
Sragovich et al. points to Javitt et al., a report on a NAP schizophrenia clinical trial, which discloses a NAP treatment protocol, wherein the NAP is prepared with pharmaceutically acceptable carrier for intranasal administration by aerosolization. See Javitt et al. at section 2.2, experimental drug protocol.
Accordingly, Sragovich et al. in light of Javitt et al. anticipates claims 36-38, 45, and 48-49.
Conclusion
11. No claim is allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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