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 .
This action is in response to the papers filed September 18, 2024.
Claims 1-20 are pending in the application as set forth in the claim set filed 09/18/2024.
Therefore, claims 1-20 are examined on the merits.
Priority
The present application is a CON of International Application No. PCT/US2023/015644 filed March 20, 2023.
Applicant’s claim for the benefit of a prior-filed parent provisional application 63/321,507 filed March 28, 2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is March 18, 2022.
Claim Objections
Claim 5 is objected to because of the following informalities:
Claim 5 has a period in line 5. This makes the claim two separate sentences. Claims must be one sentence with a period at the end.
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 1-2 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a mammal with Parkinson’s disease comprising transplanting dopaminergic neurons wherein p53 apoptosis has been suppressed, does not reasonably provide enablement for treating any subject with any disease or disorder through implanting midbrain dopamine neurons. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Breadth of the Claims and The Nature of the Invention
The claims are directed to a method of treating any subject with any disease through administration of midbrain dopaminergic neurons.
The specification discloses that the subject is “a vertebrate, such as a human or non-human animal, for example, a mammal. Mammals include, but are not limited to, humans, non-human primates, farm animals, sport animals, rodents and pets. Non-limiting examples of non-human animal subjects include rodents such as mice, rats, hamsters, and guinea pigs; rabbits; dogs; cats; sheep; pigs; goats; cattle; horses; and non-human primates such as apes and monkeys” (p. 26 of the specification).
The present claims encompass a breadth of vertebrates as well as invertebrates and non-mammalian subjects.
The specification discloses that the subject may suffer from “a neurodegenerative disorder and/or neurodegeneration of midbrain dopamine neurons. In certain embodiments, the neurodegenerative disorder is selected from the group consisting of Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and combinations thereof.” (p. 3 of the specification)
This does not encompass the entire breadth of any disease which may include diseases of the heart, lung, skin, and others, and additionally other neurological disorders such as cerebral ischemia.
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
The state of the prior art provides support for dopaminergic neuron transplants in mammals such as animal models and humans for the treatment of Parkinson’s Disease.
Hallett (Cell Reports 7, 1755–1761, June 26, 2014) teaches long term health and function of dopaminergic neurons transplanted into human patients of Parkinson’s Disease (p. 1755). Post mortem examinations demonstrated that grafted dopaminergic neurons survived for up to 14 years post-transplant (p. 1755, last paragraph).
Therefore, diseases such as Parkinson’s Disease and subjects such as humans are enabled by the state of the prior art.
The Existence of Working Examples and The Amount of Direction Provided by the Inventor
The working examples found in the specification are directed towards intracranial transplantation of dopaminergic neurons to NSG mice with adalimumab anti-TNF therapy where the mice are animal models of Parkinson’s Disease (p. 67-68).
The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to demonstrate that the broadly claimed genus of any subject with any disorder can be treated with dopaminergic neurons.
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))).
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method and therefore, limiting the claimed invention to mammals suffering from Parkinson’s Disease is proper.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness..
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4, 7, 9, 10-12, 14-17, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Studer (US20150010514; IDS Reference filed 02/03/2025) in view of Chou (2011. Cell Transplant 2011;20(9):1351-9; IDS Reference filed 01/06/2026) as evidenced by Zhu (Scientific RepoRtS | (2020) 10:1049), Suzuki (Biochemical and Biophysical Research Communications 483 (2017) 88-93), and Studer2 (WO2021203009; IDS Reference filed 02/03/2025)
Regarding claims 1-4 and 20, Studer teaches a method of engrafting in vivo for therapeutic treatment, comprising providing a population of floor plate midbrain dopamine neurons to a subject exhibiting at least one neurological symptom and suffers from a neurological order such as Parkinson’s Disease (PD) (Claim 16).
However, Studer does not teach that the p53 mediated apoptosis is suppressed via an inhibitor.
Chou teaches enhanced survival of dopaminergic neuronal transplants in models of PD through contacting the neurons with p53 inhibitor, pifithrin-α (PFT- α) (Abstract).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to combine the p53 inhibitor for treating dopaminergic neurons for transplant as taught by Chou with the midbrain dopamine neurons of Studer with a reasonable expectation of success. An artisan would be motivated to suppress the p53 mediated apoptosis through treatment with p53 inhibitor, pifithrin-α (PFT- α) as Chou teaches the treatment leads to enhanced survival in models of PD (Abstract).
Regarding claim 7, the combination of Studer and Chou make obvious claims 3 and 4 as discussed above. Moreover, while these references do not explicitly state what type of p53 inhibitor pifithrin-α is, it is evidenced by Zhu that pifithrin-α functions as a caspase inhibitor (p. 1, 2nd paragraph).
Regarding claim 9, the combination of Studer and Chou make obvious claim 3. Moreover, Studer teaches that the neurons express markers such as EN1, TH and Nurr1 (para. 0135, 0166).
Regarding claim 10, the combination of Studer and Chou make obvious claim 3. Moreover, Studer teaches that the neurons utilized are post-mitotic (para. 0218, 0271)
Regarding claim 11, the combination of Studer and Chou make obvious claim 3. Moreover, Studer teaches that the neurons are in vitro differentiated from “pluripotent or multipotent stem cells, which can include, but is not limited to, human embryonic stem cells (hESC) in addition to nonembryonic human induced pluripotent stem cells (hiPSC), somatic stem cells, stem cells from patients with a disease, or any other cell capable of lineage specific differentiation” (Abstract, para. 0046).
Regarding claim 12, the combination of Studer and Chou make obvious claim 3 and 11. Moreover, Studer teaches that the differentiation procedure comprises an activator of SHH, an inhibitor of SMAD, and an activator of Wnt (para. 0012).
Regarding claims 14 and 15, the combination of Studer and Chou make obvious claim 3 and 11-12. Moreover, Studer teaches that the differentiation procedure comprises CHIR99021 and dual SMAD inhibition via exposure to LDN-193189+SB431542 known as LSB (para. 0173, 0172).
Regarding claim 16, the combination of Studer and Chou make obvious claim 3 and 11-12. Moreover, Studer teaches utilizing SHH C25II (para. 0177).
Regarding claim 17, the combination of Studer and Chou make obvious claim 3 and 11-12. Moreover, Studer teaches utilizing bFGF (FGF2) in the cell culture medium (para. 0352).
Regarding claim 19, the combination of Studer and Chou make obvious claim 3. Moreover, while not explicitly stated, as evidenced by Suzuki, DA neurons differentiated from hiPSCs are inherently positive for CD184 (Abstract). As evidenced by Studer2, midbrain DA neurons differentiated in vitro are inherently negative for CD49e and positive for CD184 (p. 7, 1st paragraph).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Studer (US20150010514; IDS Reference filed 02/03/2025) in view of Chou (2011. Cell Transplant 2011;20(9):1351-9; IDS Reference filed 01/06/2026) as applied to claims 3 and 4, and in further view of Barnum (J Parkinsons Dis. 2014 Jan 1;4(3):349–360)
As discussed above and incorporated herein in its entirety, the combination of Studer and Chou make obvious a method of treating Parkinson’s Disease (PD) by implanting midbrain dopaminergic neurons with an inhibitor of p53 which suppresses p53 mediated apoptosis.
However, these references do not teach administering a TNF alpha inhibitor.
Barnum teaches administering TNF inhibitor XPro1595 which demonstrates in vitro and in vivo efficacy in preclinical models of PD and can significantly reduce dopaminergic neuronal death (p. 350, 2nd column). XENP345 works via the same mechanism of inhibiting TNF and has been shown to improve DA neuronal survival (p. 350, 2nd column). Barnum in particular shows that peripheral administration of XPro1595 crosses into the CNS to block glial activation and attenuate loss of DA neurons (p. 351, 1st column; p. 354, 2nd column; p. 356, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer an inhibitor of TNF alpha in place of the agent of p53 inhibitor when transplanting dopaminergic midbrain neurons to an individual with PD as taught by Studer and Chou with a reasonable expectation of success. An artisan would have been motivated to administer a TNF alpha inhibitor, thereby suppressing p53 apoptosis of the neuronal transplant as Barnum teaches that it is known in the art to administer TNF alpha inhibitors to individuals with PD and that it has been shown to improve neuronal survival (p. 350, 2nd column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Studer (US20150010514; IDS Reference filed 02/03/2025) in view of Chou (2011. Cell Transplant 2011;20(9):1351-9; IDS Reference filed 01/06/2026) as applied to claims 3 and 4, and in further view of Ghosh (PNAS, 2007, 104 (47) 18754-18759; IDS Reference filed 01/06/2022)
As discussed above and incorporated herein in its entirety, the combination of Studer and Chou make obvious a method of treating Parkinson’s Disease (PD) by implanting midbrain dopaminergic neurons with an inhibitor of p53 which suppresses p53 mediated apoptosis.
However, these references do not teach administering a Nfkb inhibitor.
Ghosh teaches a peptide which is capable of inhibiting the induction of Nfkb activation in models of Parkinson’s Disease (p. 18757, 2nd column). Ghosh further teaches that the administration of the peptide protected TH positive dopaminergic neurons and ameliorated functional impairment (p. 18757, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer an inhibitor of Nfkb as taught by Ghosh in place of the agent of p53 inhibitor when transplanting dopaminergic midbrain neurons to an individual with PD as taught by Studer and Chou with a reasonable expectation of success. An artisan would have been motivated to administer a Nfkb inhibitor, thereby suppressing p53 apoptosis of the neuronal transplant as Ghosh teaches that it is known in the art to administer nfkb inhibitors to individuals with PD and that it has been shown to provide neuronal protection and ameliorate functional impairment (p. 18757, 2nd column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Studer (US20150010514; IDS Reference filed 02/03/2025) in view of Chou (2011. Cell Transplant 2011;20(9):1351-9; IDS Reference filed 01/06/2026) as applied to claim 3, and in further view of Qi (J. Neurochem (2016) 138, 746-757).
As discussed above and incorporated herein in its entirety, the combination of Studer and Chou make obvious a method of treating Parkinson’s Disease (PD) by implanting midbrain dopaminergic neurons with an inhibitor of p53 which suppresses p53 mediated apoptosis.
However, these references do not teach suppressing the p53 mediated apoptosis via knocking out TP53.
Qi teaches p53-dependent cell death pathway exists in both human PD and experimental animal models of PD (p. 747, 1st column). Qi knocks out/deletes the p53 gene (i.e. TP53) in dopaminergic neurons which significantly reduced dopaminergic neuronal loss (Abstract, Fig 1).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize a knockout of TP53 as taught by Qi in place of the agent of p53 inhibitor when transplanting dopaminergic midbrain neurons to an individual with PD as taught by Studer and Chou with a reasonable expectation of success. An artisan would have been motivated to knock out the p53 gene, thereby suppressing p53 apoptosis of the neuronal transplant as Qi teaches knocking out p53 results in significantly reduced dopaminergic neuronal loss (Abstract, Fig 1.).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Studer (US20150010514; IDS Reference filed 02/03/2025) in view of Chou (2011. Cell Transplant 2011;20(9):1351-9; IDS Reference filed 01/06/2026) as applied to claim 3 and 11-12, and in further view of Studer3 (US20180094242A1)
As discussed above and incorporated herein in its entirety, the combination of Studer and Chou make obvious a method of treating Parkinson’s Disease (PD) by implanting midbrain dopaminergic neurons with an inhibitor of p53 which suppresses p53 mediated apoptosis. Moreover, Studer teaches that the differentiation procedure of the neurons comprises an activator of SHH, an inhibitor of SMAD, and an activator of Wnt (para. 0012).
However, regarding claim 13, the references do not teach that the at least one activator of Wnt signaling is increased between about 2 days to about 6 days.
Studer3 teaches contacting the cells with a Wnt signaling activator in the process of differentiating dopaminergic midbrain neurons in vitro, wherein the concentration is increased at 4 days after the initial contact by about 400% to 1000% of the initial concentration (para. 0006, 0081).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to increase the Wnt signaling activator in the method of Studer and Chou as taught by Studer3 with a reasonable expectation of success. An artisan would be motivated to do so as Studer3 teaches it is a known method to obtain midbrain dopaminergic neurons through in vitro differentiation.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Studer (US20150010514; IDS Reference filed 02/03/2025) in view of Chou (2011. Cell Transplant 2011;20(9):1351-9; IDS Reference filed 01/06/2026) as applied to claim 3 and 11-12, and in further view of Oosterveen (Stem Cell Reports 2021, 16: 2718-2735)
As discussed above and incorporated herein in its entirety, the combination of Studer and Chou make obvious a method of treating Parkinson’s Disease (PD) by implanting midbrain dopaminergic neurons with an inhibitor of p53 which suppresses p53 mediated apoptosis. Moreover, Studer teaches that the differentiation procedure of the neurons comprises an activator of SHH, an inhibitor of SMAD, and an activator of Wnt (para. 0012).
However, these references do not teach further contacting the cells after Wnt activation with a Wnt inhibitor.
Oosterveen teaches a method of differentiating dopaminergic neurons by contacting embryonic stem cells with an activator of Wnt, CHIR9921, from day 4 to day 13 of differentiation and then an inhibitor of Wnt, IWP2, from day 11 to day 16 (Figure 4d). This procedure resulted in robust induction of SOX6 in dopaminergic neurons (p. 2724, 2nd column). Oosterveen teaches that IWP2 induces substantia nigra-specific (an area in the midbrain) lineage markers/identity in these cultures (p. 2724, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to contact the midbrain dopaminergic neurons of Studer and Chou with a wnt inhibitor as taught by Oosterveen with a reasonable expectation of success. An artisan would have been motivated to add a Wnt inhibitor to the method of differentiation as Oosterveen teaches the inhibition of Wnt after the activation of Wnt results in specifying the lineage markers towards that of particular brain regions such as substantial nigra (p. 2724, 2nd column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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