DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 09/08/2025 is acknowledged.
Species restrictions A and B are withdrawn and claims 10 and 17 are rejoined.
Claim 20 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/08/2025.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5,7-12,16-18 and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is unclear with regard to what is encompassed by the term “fibroblast” given the terminology “dopaminergic fibroblast” in dependent claim 2. Fibroblasts do not naturally make dopamine. Example 3 supports that dopaminergic cells are neuronal.
Claims 3 and 4 are unclear by using latent language. It id not clear if the culture step of claim 1 is required to lead to neuronal cells or if the step is merely sufficient to do so.With claim 4, it is not clear if treatment activates TH or is just capable of doing so. Further dependent claims are unclear as the fail to clarify claims 1,3 or 4.
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 1-5,7-12,16-18 and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The nature of the invention relates to the treatment of Parkinson’s Disease using fibroblasts. Claim 1 is generically drawn to such treatment using “fibroblast cells”. Dependent claims refer to dopaminergic fibroblasts and fibroblasts cultured under conditions to differentiate fibroblasts into neuronal cells. No claim requires use of neuronal cells in treatment. Reciting that fibroblasts are cultured under conditions sufficient to differentiate fibroblasts into neuronal cells does not require neuronal cells be obtained or used.
Example 2 of the Specification teaches that fibroblasts can be cultured on poly-Lys coated plates in media comprising RA and BDNF and the fibroblasts become neuronal-like. Example 3 supports that these cells secrete dopamine. There is no evidence on the record that the obtained cells are sufficient to treat Parkinson’s or symptoms in a model of Parkinson’s. The claims do not require that fibroblasts secrete dopamine with exception that claim 2 recites that the fibroblasts are “dopaminergic fibroblasts”. Paragraph 30 states, “ “Dopaminergic cells” describe cells which possess a dopaminergic phenotype. A dopaminergic phenotype includes expression of one or more of tyrosine hydroxylase, aldehyde dehydrogenase 2 (ALDH2), DARPP-32, and D2 dopamine receptor.” Paragraph 31 defines “fibroblast” as, “…a cell, progenitor cell, or differentiated cell and include isolated fibroblast cells or population(s) thereof capable of proliferating and differentiating into ectoderm, mesoderm, or endoderm.” Fibroblasts do not normally express tyrosine hydroxylase and claim 2 and 4, which require the fibroblasts be “dopaminergic” (claim 2), and are contacted with an agent capable of activation tyrosine hydroxylase expression (claim 4) encompass use of agents that can activate expression of a transgene encoding tyrosine hydroxylase. The claims do not require the fibroblasts be differentiated into neuronal cells that express endogenous tyrosine hydroxylase and do not require that the cells or TH lead to dopamine production.
With regard to “administering an effective amount of a composition comprising fibroblast cells”, the specification teaches, “As one example, an effective amount is the amount sufficient to ameliorate and/or reverse Parkinson’s disease in an individual. In one example, an effective amount of cells (e.g., dopaminergic cells or fibroblasts) is an amount of cells effective to regenerate or repair neural tissue in an individual having or at risk for developing Parkinson’s disease. In another example, an effective amount of cells is an amount of cells capable of improving the behavior and/or neurological function of an individual having Parkinson’s disease” at paragraph 38. However, there are no teachings with regard to the identifying characteristics of the cells, how many of the cells, or how to deliver the cells to acquire the effects that meet the required “effective amount”. The specification does teach that cell therapy for Parkinson’s patients has been previously used, including a study wherein patients underwent stereotactic implantation of human fetal mesencephalic tissue in one caudate nucleus”. This is not seen as sufficiently enabling for transplanting fibroblasts to treat Parkinson’s. The specification only teaches how to culture fibroblasts in RA to obtain neuronal cells. Paragraph 67 discusses that dopaminergic cells generated from fibroblasts can be delivered through a cannula that has an inner stylet that penetrates the putamen. Only claim 2 requires the cells be dopaminergic and even then, “dopaminergic” is not defined as dopamine secreting but is defined as “expression of one or more of tyrosine hydroxylase, aldehyde dehydrogenase 2 (ALDH2), DARPP-32, and D2 dopamine receptor.” Mere expression of one of these enzymes or receptors does not lead to secretion of dopamine to treat symptoms. Notably, Caiazzo (NATURE | VOL476 | 11 AUGUST 2011| 224-227) taught numerous distinctive components of the dopaminergic machinery, including the distinctive components of the dopaminergic machinery, including TH, vesicular monoamine transporter 2 (VMAT2; also known as SLC18A2), dopamine transporter (DAT; also known as SLC6A3), as well as aldehyde dehydrogenase 1a1 (ALDH1A1) and calbindin (see page 225, col. 1). Thus, expression of TH alone is not sufficient to support dopamine production by the claimed fibroblasts. Importantly, Caiazzo also taught that the reprogrammed DA neurons differed from primary DA neurons with 160 genes differently expressed with a >5-fold.
Paragraph 69 states that the disclosed methods comprise treating Parkinson’s disease by providing an effective amount of fibroblasts and that the fibroblast may be dopaminergic fibroblasts. Thus, claim 1 encompasses administering any fibroblast from any source, such as skin wherein the fibroblast is not dopaminergic.
The working examples teach differentiation or trans-differentiation of fibroblasts into cells having neuron-like morphology and phenotype where the phenotype is increased NeuN staining, TH expression, The Specification teaches the neural induction was carried out in N2 media with RA and BDNF. No other means of inducing these effects was taught and no other neuronal phenotypes were taught. While TH expression was observed, the specification does not teach that any dopamine was formed. Daubner (Arch Biochem Biophys. 2010 Dec 19;508(1):1–12. doi: 10.1016/j.abb.2010.12.017) taught that tyrosine hydroxylase catalyzes the rate-limiting step in converting tyrosine into DOPA. However, it’s mere presence does not necessarily indicate that dopamine is produced. There are other steps in the biosynthetic pathway that are not necessarily present in the cells of the invention. It is also noted that no claim requires expression of TH by the cells.
Claim 1 also encompasses prevention of Parkinson’s. Treatment of an existing condition fails to correlate to preventions. Furthermore, absent 100% certainty that an individual will develop disease, one cannot determine if a disease state is prevented. The working examples fail to address prevention of Parkinson’s. Prevention or prophylaxis requires that the disease state be stopped before it has begun. The specification does not teach how to assess whether a subject will acquire a disease prior to the subject exhibiting symptoms. Once a subject exhibits a phenotype (i.e. Parkinson’s disease), the methods encompassed by the claims would meet the qualifications for treatment, but not prevention. There are no teachings or guidance in the specification with regard to which subjects would be at risk for developing a disease such that the disease can be inhibited prior to its onset or at what stage the claimed methods would be carried out to prevent onset of the phenotype.
Thus, given the breadth of the claims regarding use of any fibroblast cell, the lack of guidance with regard to whether the cells obtained by culture in N2, RA and BDNF lead to dopamine production, the lack of guidance with regard to in vivo function or effect of the cells and the guidance in the art with regard to the role of TH in dopamine synthesis, it would require undue experimentation to teach how to treat or prevent Parkinson’s using fibroblasts.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-5,7-8,10-12,16-18 and 21 are rejected under 35 U.S.C. 102a1 as being anticipated by Liu (Cell Research (2012) 22:321-332).
Claim 1 is drawn to a method of treating or preventing Parkinson’s disease and requires a single method step of administering a composition comprising fibroblast cells to an individual in need thereof. The term “fibroblast” in claim 1 is interpreted as a fibroblast that has been converted to a neuronal-type cell that produces dopamine (dopaminergic fibroblast, claim 2).
Liu taught conversion of fibroblasts into dopaminergic neuron-like cells that provided symptomatic relief in a rat Parkinson’s disease model. The neuron-like cells appear to fit the term “dopaminergic fibroblasts” (claim 2) as used in the specification. The cells were transfected with nucleic acids encoding transcription factors that directed differentiation and the cells were cultured under conditions that were sufficient to differentiate the cells into neuronal cells (claim 3). These conditions included FGF which is a neurotrophic growth factor (claims 5,7-8). The iDAs expressed TH (claims 4,11-12). The cells were delivered into the striatum of a rat model of PD (claim 16,18), which comprises the putamen (claim 17). The rat model was made using 6-OHDA, which meets the limitation of drug-induced parkinsonism (claim 21) and the limitation of non-immunologically mediated loss of endogenous dopaminergic neurons (claim 10).
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.
Claim(s) 1 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Cell Research (2012) 22:321-332) in view of Cannon (Neurobiol Dis. 2009 May ; 34(2): 279–290. doi:10.1016/j.nbd.2009.01.016) Mount and Li.
Liu meets the limitations of claim 1 as set forth above. Liu teaches a chemically induced model of Parkinson’s disease. Liu does not teach Parkinson’s disease cause by an immunologically mediated loss of endogenous dopaminergic cells.
However, Cannon taught a rotenone-induced model of Parkinson’s that reflects an immunologically-based loss of dopaminergic neurons. Mount taught that rotenone leads to an increase in IFN-g in microglia, increasing their activity and death of dopaminergic neurons that is more reflective of familial Parkinson’s disease. This model “reproduces many features of PD, including systemic mitochondrial impairment, oxidative damage, microglial activation, selective nigrostriatal dopaminergic degeneration, L-DOPA-responsive motor deficits, α-synuclein accumulation and aggregation with formation of Lewy body-like inclusions, impairment of ubiquitin-proteasome function, acidification and mitochondrial translocation of DJ-1, iron accumulation in substantia nigra and gastrointestinal dysfunction associated with α-synuclein accumulation and aggregation” (Cannon, page 7). Likewise, Li taught rotenone-induced models reproduce pathological features of Parkinson’s disease through microglial activation as a result of changes to numerous cytokines in the brain, leading to neuroinflammation and loss of dopaminergic neurons. Both Mount and Li taught administration agents that abrogate IFN- g using IFN- g antibodies (Mount) or gastrodin (Li), attenuate neuronal loss and inhibit the neuroinflammation caused by rotenone.
It would have been obvious at the time of filing to carry out the method of treatment taught by Liu on an immunologically based model of Parkinson’s disease as taught by Cannon, Mount and Li to arrive at the invention as claimed. One would have been motivated to substitute the rotenone model for the chemically induced model of dopaminergic cell death of Liu as the mechanisms of dopaminergic neuron loss in the rotenone model were more reflective of neuronal cell loss in human Parkinson’s disease. One would have had a reasonable expectation of success in carrying out the substitution as Cannon taught the rotenone model of Parkinson’s is highly reproducible and excellent tool to test new neuroprotective strategies.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632