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 .
DETAILED ACTION
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed October 29, 2025 is acknowledged. Claims 1 and 5 are amended. Claims 11-12 are newly added. Claims 1-10 and newly added claims 11-12 are pending in this application.
3. Claims 1-12 are under examination in this office action.
4. Applicant’s arguments filed on October 29, 2025 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
5. The objection to claims 1-3 and 17-20 is withdrawn in response to Applicant’s amendment to the claims.
The rejection of claims 1-10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite in response to Applicant’s amendment to the claims.
Claim Rejections/Objections Maintained
In view of the amendment filed on October 29, 2025, the following rejections are maintained.
Claim Rejections - 35 USC § 112
6. 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 1-12 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. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1-12 as amended are drawn to a method for treating or reducing probability of developing a neurodegenerative disorder associated with impaired parkin-mediated mitophagy in a subject, comprising: a. identifying a subject as having impaired parkin-mediated mitophagy, and b. administering to the subject a therapeutically effective amount of an agent that increases Nip3-like protein X (Nix)-mediated mitophagy in a cell, wherein the agent comprises a Nix polypeptide having at least 90%, 95%, 98%, 99% or 100% sequence identity to the amino acid sequence set out in SEQ ID NO:1 or a functional fragment having Nix biological activity; or an expression vector encoding the Nix polypeptide or the functional fragment having Nix biological activity; or phorbol myristate acetate (PMA).
The claims encompass a method of treating and preventing all forms of neurodegenerative diseases associated with impaired parkin-mediated mitophagy or reducing probability of developing all forms of neurodegenerative diseases associated with impaired parkin-mediated mitophagy using an agent comprising a Nix polypeptide, a variant with at least 90% identity to instant SEQ ID NO:1 or functional fragment thereof, or an expression vector thereof; or in combination with a GABARAP-L1 polypeptide, a variant with at least 90% identity to instant SEQ ID NO:3 or functional fragment thereof, or an expression vector thereof in view of paragraphs [0073]-[0074] of the published application.
Response to Arguments
On p. 6-8 of the response, Applicant argues that: i) the rejection has been overcome in view of amendment to the claims by reciting “a neurodegenerative disorder associated with impaired parkin-mediated mitophagy” and specific Nix and GABARAP-1 sequences; ii) the specification showed 1) a human patient comprising a homozygous parkin mutation carrier who had no functional parkin protein (carrier) and yet healthy whereas the patient’s daughter carrying two heterozygous mutations manifested early onset Parkinson’s disease (figures 1-5); 2) the carrier preserved mitochondrial functional through the upregulation of Nix. Applicant further cites paragraphs [0009], [0014], [0116] and [0117] and Examples 1-10 of the specification and figures 1 and 4-5 in support of the arguments.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2164, MPEP §§2164.01-2164.06(b) & 2164.08, neither the specification nor the prior art provides sufficient guidance to enable a skilled artisan to practice the claimed invention without undue experimentation because of the following:
i. The specification provides no working example or guidance that administration of the claimed agent comprising a Nix polypeptide, variant thereof with at least 90% identity to SEQ ID NO:1 or an expression vector thereof or PMA can prevent a person from getting all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by any possible mechanisms.
The claims encompass methods of treating and preventing all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy by the claimed agent because the definition of “treating” encompasses preventing neurodegenerative diseases, and the recitation “reducing the probability of developing a neurodegenerative disease” also encompasses preventing a person from getting a neurodegenerative disease in view of paragraphs [0073]-[0074] of the published Application.
[0073] As used herein, the terms “treatment” or “treating” mean: (1) improving or stabilizing the subject's condition or disease or (2) preventing or relieving the development or worsening of symptoms associated with the subject's condition or disease.
[0074] As used herein, the terms “prevent,” “preventing,” “prevention,” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.
However, the specification provides no guidance as to how to prevent a person from getting all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy by the claimed agent before the disorders occur. The specification provides no guidance that administration of the claimed agent comprising a Nix polypeptide, variant thereof with at least 90% identity to SEQ ID NO:1 or an expression vector thereof or PMA can prevent a person from getting all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including AD and PD caused by any possible mechanisms. For example, AD and related diseases cannot be prevented, as evidenced by Van Cauwenberghe et al. (Genet Med, 2016; 18: 421-430; see p. 421, 1st paragraph, cited previously) or PD as evidenced by Oertel (F1000Res. 2017 Mar 13;6:260; see p.2 of 14, second paragraph, cited previously).
ii. There is no well-established correlation or nexus between a specific mutation in parkin gene and development of PD or even development of other neurodegenerative disorders associated with impaired parkin-mediated mitophagy.
As admitted by Applicant on p.7 of the response, a patient who carries a homozygous loss-of-function mutation in parkin gene was healthy and with no PD; whereas a patient who has parkin deficient and carries two heterozygous mutations in parkin showed early onset PD. The data shown in the specification indicates that there is no well-established correlation or nexus between a specific mutation in parkin gene and development of PD. It is unpredictable whether the mutations in parkin gene found in a subject have PD or even other undefined neurodegenerative diseases associated with impaired parkin-mediated mitophagy.
iii. The specification provides no well-established correlation between the cells isolated from an individual with PD and carrying heterozygous mutations in parkin or the cells isolated from an individual with PD and carrying a homozygous mutation in PINK1 in vitro, and the pathogeneses or causes of all forms neurodegenerative diseases associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by any possible mechanisms in vivo because of the complexity of the disease and deficiency of characterized cognition (see p. 403, abstract. Anger. Neurotoxicology 1991. 12: 403-13; see p.261, summary, Falkenburger et al., J. Neural. Transm, 2006; 70:261-268; see p. 106, 1st col, 2nd paragraph, Tayebati, Mech. Ageing Dev. 2006. 127: 100-8; and see p. 645, abstract, Sarter, Neurosci. and Biobehav. Rev. 2004. 28: 645-650, cited previously).
There is no well-established structural and functional relationship or correlation between in vitro cells isolated from an individual carrying a homozygous loss-function mutation in parkin but having no Parkinson’s disease (PD) and causes/pathogeneses of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy.
There is no well-established structural and functional relationship or correlation between in vitro cells isolated from an individual carrying heterozygous mutations in parkin and having PD and causes/pathogeneses of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy.
There is also no well-established structural and functional relationship or correlation between in vitro cells isolated from an individual carrying homozygous mutations in PINK1 and having PD and causes/pathogeneses of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy.
iii. The specification provides no actual therapeutic data from human patients or from an art-accepted animal model for AD, PD, HD, ALS or any of the other central nervous system diseases encompassed by the instant claims.
The specification provides no well-established correlation between the effects of overexpression of wild type Nix polypeptide in cells isolated from an individual with PD and carrying heterozygous mutations in parkin or the cells isolated from an individual with PD and carrying a homozygous mutation in PINK1, and the treatment of all forms neurodegenerative diseases associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by any possible mechanisms in vivo using the claimed agent comprising a Nix polypeptide, variant thereof with at least 90% identity to instant SEQ ID NO:1 or a functional fragment thereof, or an expression vector thereof, or in combination with a GABARAP-L1 polypeptide, variant thereof with at least 90% identity to instant SEQ ID NO:1 or a functional fragment thereof or an expression vector thereof, or PMA.
The specification provides no working examples or guidance to demonstrate that administration of the claimed agent can treat all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including cognitive dysfunction or dementia in AD, PD, HD, MS and ALS caused by any possible mechanisms.
The data shown in the specification only indicated that:
i) For the cells isolated from an individual carrying a homozygous loss-of-function mutation in parkin gene but with no PD:
1. Nix siRNA impaired carbonyl cyanide 3-chlorophenyihydrazone (CCCP)-induced mitophagy in the cells in vitro (see Example 5, FIG. 5A-F); 2)
2. over-expression of Nix restored CCCP-induced mitophagy in the cells in vitro (see Example 8, Figures 9A-C);
ii) For the cells isolated from an individual with PD and carrying heterozygous mutations in parkin gene:
Nix knockdown by Nix siRNA in the cells abrogated restoration of CCCP-induced mitophagy by an agent which induces Nix expression in the cells in vitro (Example 6, FIG. 7A-B).
augmented expression of Nix in the cells restored CCCP-induced mitophagy in the cells in vitro (see Example 8, FIG. 9A-C);
Over-expression of Nix rescues mitochondrial function in the cells in vitro (See Example 8, FIG. 10).
iii) For the cells isolated from an individual with PD and carrying homozygous mutations in PINK1 at c.1309T>G (p.W437G) “PINK1mut”:
specific induction of Nix in the cells by xx restored mitophagy in cells in vitro. (See Example 6, FIG. 7A-B);
Nix knockdown by Nix siRNA in the cells abrogated restoration of CCCP-induced mitophagy by an agent which induces Nix expression in vitro (see Example 7; FIG. 8A-B);
Over-expression of Nix in the cells restored CCCP-induced mitophagy in the cells in vitro (see Example 8, Figures 9A-C); and
Over-expression of Nix in the cells rescues mitochondrial function in the cells in vitro (See Example 8, FIG. 10).
The in vitro data of restoration of CCCP-induced mitophagy by overexpression of Nix in the cells isolated from an individual with no PD and carrying a homozygous loss-of-function mutation in parkin, an individual with PD and carrying heterozygous mutations in parkin, or an individual with PD and carrying homozygous mutations in PINK1 at c.1309T>G (p.W437G) “PINK1mut” shown in Examples of the specification are not an art-accepted animal model for evaluation of treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy by the claimed agent in vivo because of complexity, unpredictability of the diseases and failure to provide support a correlation between the effects from in vitro cellular data and the treatment of the diseases in vivo.
Nix-mediated mitophagy or parkin-mediated mitophagy shown in the cells in vitro is not the only cause for the diseases. For example, for PD, in addition to PINK1 and PARKIN mutations shown in the specification, there are several other causative genes linked to mitochondrial dysregulation or for PD linked to mitochondrial dysregulation including LRRK2, DJ1, ATP13A2 and SCNA and other PD risk genes. For AD, Nix-mediated mitophagy or parkin-mediated mitophagy, Abeta accumulation and/or hyperphosphorylated tau is not the only cause of cognitive dysfunction or dementia in AD. Several factors and genes are involved in pathogenesis of AD including ageing, inflammation and immune response, APP, presenilin1/2, ApoE and genes involved in the amyloid cascade, genes involved in the mitochondrial cascade as taught by Swerdlow (p. 348-344, Swerdlow, Clin. Interv. Ageing 2007; 2:347-359, cited previously), Atwood et al. (p. abstract; Atwood et al., J. Alzheimer’s Disease; 2015; 47:33-47, cited previously) and Henstridge et al. (p. 95-103; Henstridge et al., Nat. Rev. Neurosci. 2019; 20: 94-107, cited previously). Thus, it is unpredictable whether administration of the claimed agent can treat all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including cognitive dysfunction or dementia, AD, PD, HD, MS and ALS caused by any possible mechanisms, indicating that undue experimentation is required by a skilled artisan to perform while practicing the claimed method.
iv. The specification provides no well-established structural and functional relationship or correlation between the wild type Nix polypeptide of instant SEQ ID NO:1 or GABARAP-L1 polypeptide of instant SEQ ID NO:3 and the claimed variants with at least 90% identity to instant SEQ ID NO:1 or the claimed structurally and functionally undefined functional fragments having a Nix biological activity or in combination with the claimed variants with at least 90% identity to instant SEQ ID NO:3 or structurally and functionally undefined functional fragments having GABARAP-L1 biological activity or an expression vector thereof or PMA in restoring CCCP-induced mitophagy in the cells isolated from an individual with PD and carrying heterozygous mutations in parkin or cells isolated from an individual with PD and carrying a homozygous mutation in PINK1 in vitro, or even in treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by all possible mechanisms in vivo.
The specification also fails to teach what other specific structures, amino acid sequences and/or features are required by the claimed structurally and functionally undefined variants or functional fragments of Nix polypeptide or in combination with the claimed structurally and functionally undefined variants or functional fragments of GABARAP-L1 in restoring CCCP-induced mitophagy in the cells in vitro or even in treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by all possible mechanisms. Thus, a skilled artisan cannot contemplate how to make and use the claimed invention without undue experimentation.
Note that the scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without such guidance, it is unpredictable whether all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including cognitive dysfunction or dementia, AD, PD, HD, MS and ALS caused by any possible mechanisms can be treated by the claimed agent comprising a Nix polypeptide, variant with at least 90% identity to instant SEQ ID NO:1 or functional fragment thereof or an expression vector thereof, or in combination with a GABARAP-L1 polypeptide, variant with at least 90% identity to instant SEQ ID NO:3 or functional fragment thereof or an expression vector thereof, or PMA; and thus the experimentation left to those skilled in the art is extensive and undue. See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Int. 1986). Thus, the skilled artisan cannot readily know how to use the claimed invention as currently claimed without further undue experimentation. In re Marzocchi, 439 F.2d 220, 223-24,
169 USPQ 367, 369-70 (CCPA 1971)” See MPEP § 2164.03.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, no working examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by a skilled artisan to perform in order to practice the claimed invention as it pertains to a method for treating or reducing probability of developing a neurodegenerative disorder associated with impaired parkin-mediated mitophagy in a subject by administration of the claimed agent comprising .
Accordingly, the rejection of claims 1-12 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of enablement and the rejection of claims 1-12 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of written description requirement are maintained.
Claim Rejections - 35 USC § 112
7. Claims 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1-12 encompass using a genus of agents comprising a genus of Nix polypeptide or variant thereof having at least 90%~100% identical to instant SEQ ID NO:1 or a genus of functional fragment having Nix Biological activity, or a genus of expression vector thereof for treating or reducing probability of developing a genus of neurodegenerative disorder associated with impaired parkin-mediated mitophagy in a subject. Claims 11-12 encompass using the claimed genus of Nix polypeptide and a genus of GABARAP-L1 polypeptide or variants thereof having at least 90%...100% identity to the amino acid sequence set out in SEQ ID NO:3 or functional fragment having GABARAP-L1 biological activity or a genus of expression vector thereof for treating or reducing probability of developing a genus of neurodegenerative disorder associated with impaired parkin-mediated mitophagy in a subject.
Applicant has not disclosed sufficient species for using the broad genus of agent, the broad genus of Nix polypeptide or variants or functional fragments thereof, the broad genus of GABARAP-L1 polypeptide or variants or functional fragments thereof, or the broad genus of an expression vector encoding thereof for treating and reducing probability of developing the broad genus of neurodegenerative diseases associated with impaired parkin-mediated mitophagy.
Response to Arguments
On p. 6-8 of the response, Applicant argues with the same arguments set forth above.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2163, MPEP §§2163.01-2163.03, the specification fails to provide sufficient description or information or evidence to demonstrate that Applicant is in possession of using the claimed genus of agent comprising a genus of Nix polypeptide or variants thereof with at least 90% identity to instant SEQ ID NO:1 or a genus of functional fragment thereof or an expression vector thereof or in combination with a GABARAP-L1 polypeptide or a genus of variants thereof having at least 90%...100% identity to the amino acid sequence set out in SEQ ID NO:3 or functional fragment having GABARAP-L1 biological activity for treating or reducing probability of developing a genus of neurodegenerative disorder associated with impaired parkin-mediated mitophagy in a subject because of the following:
i. There is no well-established structural and functional relationship or correlation between the claimed genus of agent comprising a Nix polypeptide, a genus of variant with at least 90% identity to instant SEQ ID NO:1, a genus of functional fragment thereof, a genus of expression vector encoding thereof and the wild type of Nix polypeptide of instant SEQ ID NO:1 in in restoring CCCP-induced mitophagy in the cells isolated from an individual carrying heterozygous mutations in parkin with PD or cells isolated from an individual carrying a homozygous mutation in PINK1 with PD in vitro, or even in treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by all possible mechanisms in vivo.
There is no well-established structural and functional relationship or correlation between the claimed genus of agent comprising a GABARAP-L1 polypeptide or a genus of variants thereof having at least 90%...100% identity to the amino acid sequence set out in SEQ ID NO:3 or functional fragment having GABARAP-L1 biological activity for treating or reducing probability of developing a genus of neurodegenerative disorder associated with impaired parkin-mediated mitophagy and the wild type GABARAP-L1 in in restoring CCCP-induced mitophagy in the cells isolated from an individual carrying heterozygous mutations in parkin with PD or cells isolated from an individual carrying a homozygous mutation in PINK1 with PD in vitro, or even in treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by all possible mechanisms in vivo.
ii. The specification has not disclosed sufficient species for using the claimed genus of agent comprising a Nix polypeptide, variant or functional fragment thereof, or an expression vector thereof, or in combination with a GABARAP-L1 polypeptide, variant or functional fragment thereof or an expression vector thereof in restoring CCCP-induced mitophagy in the cells isolated from an individual carrying heterozygous mutations in parkin with PD or cells isolated from an individual carrying a homozygous mutation in PINK1 with PD in vitro, or even in treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by all possible mechanisms in vivo.
iii. The specification fails to teach the detailed structures and sequences and characteristics for the claimed agent comprising a variant with at least 90% identity to instant SEQ ID NO:1 or functional fragment thereof or an expression vector or in combination with a variant with at least 90% identity to instant SEQ ID NO:3 or functional fragment thereof or an expression vector thereof in restoring CCCP-induced mitophagy in the cells isolated from an individual carrying heterozygous mutations in parkin with PD or cells isolated from an individual carrying a homozygous mutation in PINK1 with PD in vitro, or even in treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by all possible mechanisms in vivo.
The specification fails to teach what other structures/amino acid sequences can or cannot be included/changed in the claimed variant with at least 90% identity to instant SEQ ID NO:1 or functional fragment thereof or an expression vector or in combination with the claimed variant with at least 90% identity to instant SEQ ID NO:3 or functional fragment thereof or an expression vector thereof in restoring CCCP-induced mitophagy in the cells isolated from an individual carrying heterozygous mutations in parkin with PD or cells isolated from an individual carrying a homozygous mutation in PINK1 with PD in vitro, or even in treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy including all forms of AD, PD, HD, MS and ALS caused by all possible mechanisms in vivo.
Since the common characteristics/features of other variants with at least 90% identity to instant SEQ ID NO:1 or functional fragment thereof or an expression vector or in combination with the claimed variants with at least 90% identity to instant SEQ ID NO:3 or functional fragment thereof or an expression vector thereof are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention in view of Burgess et al. (J of Cell Bio. 1990, 111:2129-2138, cited previously), Pawson et al. (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452, cited previously), Alaoui-lsmaili et al. (see p. 502, right col., 2th paragraph; Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507, cited previously) and Guo et al. (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210, cited previously).
iv. As stated in M.P.E.P. § 2163(II)(A)(3), a specification may describe an actual reduction to practice by showing that the inventor constructed an embodiment or performed a process that met all the limitations of the claim and determined that the invention would work for its intended purpose. Cooper v. Goldfarb, 154 F.3d 1321,1327, 47 USPQ2d 1896, 1901 (Fed. Cir. 1998). See also UMC Elecs. Co. v. United States, 816 F.2d 647, 652, 2 USPQ2d 1465, 1468 (Fed. Cir. 1987) (“[T]here cannot be a reduction to practice of the invention ... without a physical embodiment which includes all limitations of the claim.”); Estee Lauder Inc. v. L’Oreal, S.A., 129 F.3d 588, 593, 44 USPQ2d 1610, 1614 (Fed. Cir. 1997) (“[A] reduction to practice does not occur until the inventor has determined that the invention will work for its intended purpose.”); Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1578, 38 USPQ2d 1288, 1291 (Fed. Cir. 1996) (determining that the invention will work for its intended purpose may require testing depending on the character of the invention and the problem it solves).
To demonstrate the reduction to practice of a method of treating or reducing probability of developing a neurodegenerative disorder associated with impaired parkin-mediated mitophagy in a subject by administration of the claimed agent requires either a working embodiment, a demonstration of operability in the treatment of an art accepted animal model of the condition to be treated wherein that animal model has been shown to be reliably predictive of efficacy in the treatment of the condition, or a demonstration that the therapeutic agent employed therein possesses an activity in which the majority of the claimed agent including variants or functional fragments of Nix of SEQ ID NO:3 and/or GABARAP-L1 of instant SEQ ID NO:3 possessing the activity have been shown to be effective in the treatment of the condition. In the instant case, Applicant has provided none of these. Consequently, Applicant has failed to demonstrate possession of the claimed method or even a single species of using the genus of agent comprising a Nix of SEQ ID NO:3 and/or GABARAP-L1 of instant SEQ ID NO:3 or variants or functional fragments thereof, or an expression vector thereof or PMA for treating or reducing probability of developing a neurodegenerative disorder associated with impaired parkin-mediated mitophagy in a subject required thereby as of the earliest effective filing date of the instant application.
Applicant has failed to demonstrate a reduction to practice of a representative number species of using the claimed genus of agent in a method for treating or reducing probability of developing a neurodegenerative disorder associated with impaired parkin-mediated mitophagy by the administration of such agent comprising a Nix of SEQ ID NO:3 and/or GABARAP-L1 of instant SEQ ID NO:3 or variants or functional fragments thereof, or an expression vector thereof or PMA. The experimental results described in the specification consist primarily of the characterization of the effects of Nix of instant SEQ ID NO:1 and/or GABARAP-L1 of instant SEQ ID NO:3 in CCCP-induced mitophagy in cells isolated from an individual with no PD and carrying a homozygous loss-of-function mutation in parkin, cells isolated from an individual with PD and carrying heterozygous mutations in parkin or cells isolated from an individual with PD and carrying a homozygous mutation in PINK1 in vitro.
The effects from the in vitro cells shown in the specification do not reflect the treatment of all forms of neurodegenerative disorders associated with impaired parkin-mediated mitophagy in a subject in vivo using the claimed genus of agent, and are not an animal model for evaluating the effectiveness of an agent in treatment of a neurodegenerative disorder associated with impaired parkin-mediated mitophagy in a subject in view of Anger (1991), Falkenburger et al. (2006), Tayebati (2006) and Sarter (2004) for the reasons set forth above.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of agent for treating or reducing probability of a neurodegenerative disease associated with impaired parkin-mediated mitophagy in vivo, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed method has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Accordingly, the rejection of claims 1-12 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 is maintained.
Conclusion
8. NO CLAIM IS ALLOWED.
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Geisler et al. (Autophagy, 6:7, 871-878, 2010, as in IDS) teaches that mitochondrial dysfunction is an early sign of many neurodegenerative diseases and that two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). Geisler teaches that PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps (see abstract). Geisler teaches mitochondrial dysfunction has been connected to virtually all neurodegenerative diseases (p.871, first paragraph). Geisler teaches an investigation into the localization and functional impact of PD-associated PINK1 mutations on Parkin- dependent mitophagy as well as the reciprocal capabilities of PINK1 and Parkin mutants to physically associate (see p.872, first full paragraph).
Rubinsztein (WO 2004/089369 as in IDS) teaches a method for treating a neurodegenerative disorder in a subject with impaired parkin-mediated mitophagy, comprising administering to the subject a therapeutically effective amount of an agent that increases Nix-mediated mitophagy in a cell, i.e. rapamycin (see e.g. abstract), and wherein the cell can be a neuron (see e.g. p.57, lines 21-30); and wherein the neurodegenerative disorder is associated with mitochondrial dysfunction, including PD (mutation in parkin gene, which causes reduced expression of parkin and/or PINK1), AD, Lewy body dementia, HD (see p.4, lines 29-33).
Rodriguez (US2004/0253223 as in IDS) teaches a method for treating a neurodegenerative disorder, including AD, comprising administering a therapeutically effective amount of phorbol myristate acetate (see paragraphs [0037]-[0040]; claims 1, 10 and 14 and).
Le Grand et al. (Autophagy. 2011; 7:10980-1107, as in IDS) teaches the role of GABARAPL1 in autophagy, specifically in respect to neurodegeneration; in particular, a decreased GABARAPL1 activity is required for neurodegenerative conditions to progress; and that the potential role of the interaction of Nix and GABRAPL1 in clearing damaged mitochondria/mitophagy and the potential use of Nix and GABRAPL1 polypeptides and vectors encoding the polypeptides (see Fig 1, Fig 2, Table 1 and pp.1098-1999).
10. THIS ACTION IS MADE FINAL. 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.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Chang-Yu Wang
February 25, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675