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 with traverse of Species A (i.e., a single and specific therapeutic to be administered as a polynucleotide encoding a mammalian YAP polypeptide comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 1) in the reply filed on October 27, 2025, is acknowledged. Although Applicant elected with traverse, no arguments regarding Applicant’s traversal have been provided.
The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Claims 1-4 were originally filed on June 7, 2022.
The amendment received on June 7, 2022, amended claims 1-4; and added new claims 5-6.
Claims 1-6 are currently pending and under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/JP2020/029677 filed August 3, 2020, and claims priority under 119(a)-(d) to Japanese Application No. 2019-145259 filed on August 7, 2019.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for Japanese Application No. 2019-145259, which papers have been placed of record in the file. Please note that the Japanese application is in a foreign language and therefore cannot be verified.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on June 7, 2022; November 15, 2022; August 30, 2023; September 1, 2023; August 9, 2024; and August 13, 2024, are being considered by the examiner.
Sequence Interpretation
For claim 2, please note that the Examiner is interpreting the scope as open-ended requiring at least 80% identity to SEQ ID NO: 1 with any N- and/or C-terminal additions. Since SEQ ID NO: 1 has a length of 366 amino acids, the scope of claim 2 encompasses up to 72 modifications including substitutions, deletions and/or insertions. Thus, a polynucleotide that encodes this sequence encompasses polynucleotides that encode any sequence with up to 72 amino acid modifications.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 1, with respect to “a substance capable of increasing an amount of mammalian YAP in a nucleus of a brain neuron”, it is noted that the instant specification teaches that the mammalian YAP-enhancing substance is not particularly limited as long as the substance is capable of increasing an amount of mammalian YAP in a nucleus of a brain neuron by an action of promoting the translocation of the mammalian YAP into a brain neuron nucleus, action of enhancing the expression of the mammalian YAP in a brain neuron nucleus, or the like (e.g., a polypeptide such as an antibody, a polynucleotide, a saccharide, a lipid, an organic or inorganic compound) (See instant, [0044]). As such, the scope of the claimed substance recited in claim 1 encompasses any agent having any structure/sequence. The claimed substance is only limited functionally. Since there is no claimed required core structure or sequence and the substance only needs to be capable of the claimed function but is not required, the claimed substance encompasses any substance unless there is evidence that the substance is incapable of increasing an amount of mammalian YAP in a nucleus of a brain neuron.
With respect to “preventing or treating mild cognitive impairment”, pursuant to MPEP 2111, the pending claims must be "given their broadest reasonable interpretation consistent with the specification." The Federal Circuit’s en banc decision in Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) expressly recognized that the USPTO employs the "broadest reasonable interpretation" standard:
The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must "conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description so that the meaning of the terms in the claims may be ascertainable by reference to the description." 37 CFR 1.75(d)(1).
In the instant case, it is noted that the instant specification states that “prevention of mild cognitive impairment” (MCI) includes the prevention of the development of MCI as well as the prevention of the symptomatic worsening of MCI (See instant, [0028]). However, the instant specification does not define what is meant by “prevention of the development of MCI”. Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. As such, since the instant specification does not define what is meant by “prevention of the development of MCI”, the plain and ordinary meaning of the term “prevention” applies. “Prevent” is defined as to keep from happening or existing (See Merriam-Webster, “Prevent”, Merriam-Webster, available online at https://www.merriam-webster.com/dictionary/prevent, 9 pages (accessed on 2025) at pg. 1). As such, the scope of “preventing” MCI encompasses 100% prevention where MCI would not occur at all. Regarding the instant specification stating that prevention includes the prevention of the symptomatic worsening of MCI is being interpretated such that a subject already has/suffered from MCI but prevention of symptomatic worsening correlates to treating MCI or reducing the worsening of MCI. Thus, “preventing” MCI encompasses 100% prevention of MCI.
It is noted that the instant specification provides evidence demonstrating that S1P as a substance and instant SEQ ID NO: 1 (i.e., a modified mammalian YAP with a truncated C-terminus and an inserted mini-exon between exons 5 and 6 as taught by Fujita et al., Nature Comm. 8:1-15 (2017) at pg. 2, col. 2, 2nd paragraph) 100% prevents MCI. More specifically, the specification discusses that high necrotic cell numbers were seen in MCI patients when compared to healthy control patients and AD patients, and examined the number of necrotic cells in brain neurons in two types of AD mouse models, i.e., 5xFAD mice and APP-KI mice) where the number of necrotic cells increased from 1 to 6 months of age whereas the number of necrotic cells decreased after 6 months of age (See instant, [0082], [0084], Figures 5A-C). As such, these results were interpreted such that around 6 months reflect the condition (symptoms) of MCI, before 6 months of age, i.e., at 1 month of age, reflects the condition before MCI development or at a very early stage after MCI development, and after 6 months of age reflect the condition (symptoms) of AD patients (See instant, [0085]). Moreover, the specification teaches that the expression of nuclear YAP was detected in the healthy patients whereas the amounts of nuclear YAP were decreased in the AD patients and further decreased in the MCI patients (See instant, [0088]; Figures 1 and 9A). Instead, it was found that YAP was cytoplasmically colocalized with amyloid beta in AD and MCI patient brain neurons (See instant, [0088]; Figure 8A). It is known that when LATS1 is phosphorylated at Ser909, it suppresses the nuclear translocation of YAP, which correlated with the finding that AD and MCI patients had higher pLATS1 levels when compared to the control patients (See instant, [0088]; Figure 8A and 9B). Furthermore, It is known that S1P suppresses the phosphorylation of LATS1 via the S1P receptor thereby necessarily resulting in YAP nuclear translocation, which in turn, suppresses Hippo-pathway dependent necrosis (See instant, [0091]). As such, S1P or instant SEQ ID NO: 1 was administered to 5xFAD mice at1 month of age (i.e., indicated supra as reflecting the condition before MCI development or at a very early stage after MCI development) (See instant, [0092]). As a result, the amount of nuclear YAP in brain neurons had been increased and/or restored to the levels of normal mice at 6 months of age (i.e., indicated supra as reflecting the condition (symptoms) of MCI) (See instant, [0092]; Figure 10). Figure 11C and D depict that S1P and SEQ ID NO: 1 administration reduced extracellular Aβ level in 5xFAD mice at 6 months of age (See instant, [0092]). Moreover, the administration of S1P or instant SEQ ID NO: 1 also significantly resolved ER dilation of 5xFAD mice at 1 month of age, significantly resolved ER stability of 5xFAD mice at 1 month of age, and restored ER to the state of normal mice (See instant, [0092]; Figures 12-15). pSer46-MARCKS levels, which are known to be elevated by HMGB1 released by necrotic cells, were decreased to the levels of normal mice at 6 months of age as depicted in Figure 16 (See instant, [0095]; Figure 16). Figure 17 depicts that S1P and SEQ ID NO: 1 administration improved cognitive functions based on score of alternation behavior back to normal levels (See instant, [0097], [0099]; Figure 17). As such, in light of the evidence provided in the specification demonstrating that S1P and instant SEQ ID NO: 1 improved, restored and/or precluded development of MCI in the 5xFAD mouse model such that the patients given the agents exhibited levels similar to those in healthy patients, Applicants have satisfied the enablement requirement. However, as will be further articulated below, the specification enables an ordinary skilled artisan to practice the claimed invention when the mammalian YAP is instant SEQ ID NO: 1 or a lysophospholipid such as S1P and a S1P receptor agonist as a substance, but not other mammalian YAPs or substances.
Regarding what constitutes MCI, it is noted that the instant specification states that MCI means a condition that has decline in cognitive function, which does not satisfy the diagnostic criteria of dementia (in other words, has no dementia), and finds no problem in fundamental daily life or social life; and/or a condition having an elevated concentration of HMGB1 in cerebrospinal fluid as compared with a control subject having no mild cognitive impairment (See instant, [0046]). In this context, “have decline in cognitive function, which however does not satisfy the diagnostic criteria of dementia” means that the score of MMSE (mini mental state examination) falls with the range of 19 to 27; and/or the score of CDR (clinical dementia rating) is 0.5 (See instant, [0046]). Examples of dementia include Alzheimer’s disease (AD), dementia that develops in Parkinson’s disease, Lewy body dementia, and dementia that develops in progressive non-fluent aphasia (See instant, [0047]). Thus, the claimed patient population to be treated are limited to those that fall within this definition where the patient population excludes any that are diagnosed with dementia.
For claims 3 and 5, with respect to what constitutes a “control subject without MCI”, it is noted that the instant specification states that this subject can be an individual having no MCI (a control of a test subject), i.e., an individual who satisfies at least one of the following criteria: (1) no decline in cognitive function is found; (2) the diagnostic criteria of dementia are satisfied; and (3) there is a problem in fundamental daily life or social life (See instant, [0048]). As pointed out by the specification, examples of control subjects include a healthy individual and one having a disease other than MCI such as AD, multiple sclerosis, systemic lupus erythematosus, lung cancer, peripheral neuropathy, and alcoholism (See instant, [0048]). Thus, a control subject is limited to one that falls within the aforementioned category.
Claim Objections
Claims 1-2 are objected to because of the following informalities: the recite, “mammalian YAP” Although, the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner respectfully requests that Applicant uses Yes-associated protein (YAP) for the first recitation, thereafter YAP may be utilized. Appropriate correction is required.
Claims 3 and 5 are objected to because of the following informalities: the recite, “an elevated concentration of HMGB1”…. Although, the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner respectfully requests that Applicant uses High Mobility Group Box 1 (HMGB1) for the first recitation, thereafter HMGB1 may be utilized. 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 1-6 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. NOTE: this rejection is based on a mammalian YAP protein sequence and a polynucleotide sequence encoding thereof.
Independent claim 1 includes a “mammalian YAP or a polynucleotide encoding mammalian YAP”. Dependent claim 2 includes where the mammalian YAP is a polypeptide comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 1. As such, a mammalian YAP, and thus, a polynucleotide that encodes it, encompasses a vast array of polypeptide and polynucleotide sequences. As discussed in the “Sequence Interpretation” section supra, SEQ ID NO: 1 has 366 total amino acids thereby encompassing up to 72 amino acid modifications including any substitutions, deletions, and/or insertions. Moreover, the specification teaches that a mammalian YAP also includes fragments. More specifically, the specification teaches that the number of amino acid residues of the mammalian YAP is not particularly limited (See instant, [0031]). As such, the mammalian YAP of claim 1 encompasses a fragment of any YAP protein and nucleic acid sequence. Thus, the mammalian YAP of claims 1 and 3-4 encompasses any full length naturally occurring YAP protein derived from any mammal, any fragment thereof thereby including a fragment with a single deleted residue at the N- or C-terminus to any dipeptide (i.e., any two contiguous residues), any variant/analogue thereof thereby including sequences with any number of substitutions, deletions and/or insertions without requiring a core structure or sequence shared among species of the claimed genus. Similarly, the mammalian YAP of claims 2 and 5-6 encompasses any sequence with up to 72 amino acid modifications including any substitutions, deletions, and/or insertions relative to SEQ ID NO: 1 without requiring a core structure or sequence shared among species of the claimed genus. Plus, since the polynucleotide encodes the mammalian YAP, and it is well-known that a polynucleotide sequence includes further variability given the multiple codons for each residue, a polynucleotide sequence encompasses a broader scope of sequences than the protein sequences. In addition to certain structural manipulations of a mammalian YAP protein, the protein must also exhibit the function of the native YAP in order to treat MCI in a subject. Therefore, there is an enormous array of polypeptide and polynucleotide sequences encompassed without a core structure or sequence necessary for the polypeptide and/or polynucleotide encoding the polypeptide to exhibit the function of the native YAP in order to treat MCI in a subject.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Finch-Edmondson et al. teaches that YAP is a transcriptional co-activator that functions as an effector for the mammalian Hippo signaling pathway (See Finch-Edmondson et al., Biochem. Biophys. Rep. 6:24-31 (2016) at pg. 24, col. 1, 1st paragraph). YAP promotes growth and cell survival by regulating genes involved in proliferation, and interacts with many proteins via several protein-interaction domains to facilitate nuclear localization, DNA-binding and recruitment of transcription factors (See Finch-Edmondson, pg. 24, col. 1, 1st paragraph to col. 2, 1st paragraph). The human YAP1 gene comprises nine exons, generating at least eight alternatively spliced isoforms, all of which are detectable in several human tissues (See Finch-Edmondson, pg. 24, col. 2, 2nd paragraph). The YAP protein comprises multiple domains that enable biding to a variety of proteins (See Finch-Edmondson, pg. 24, col. 2, 2nd paragraph). Exons 1-3 encode the N-terminal region including the TEAD-binding and first WW domains whereas YAP’s second WW domain, which is only present in human YAP1-2 isoforms is encoded by exon 4 (See Finch-Edmondson, pg. 24, col. 2, 2nd paragraph). The C-terminal region of YAP, rich in serine, threonine and acidic amino acids, act as a strong transcription activation domain (TAD) (See Finch-Edmondson, pg. 24, col. 2, 2nd paragraph to pg. 25, col. 1, 1st paragraph). YAP does not possess a traditional nuclear localization signal, and thus, relies on association with other proteins via its PDZ-binding motif to mediate nuclear localization (See Finch-Edmondson, pg. 25, col. 1, 1st paragraph). YAP’s C-terminal TAD and PDZ-binding motifs are encoded by exons 5-9 (See Finch-Edmondson, pg. 25, col. 1, 1st paragraph). Figure 1 depicts the gene structure and transcriptional activation domain variations of human YAP isoforms (See Finch-Edmondson, pg. 25, Figure 1). Finch-Edmondson et al. also teaches that human YAP isoforms exhibit different functions. For example, overexpression of human YAP1-2γ promoted cellular proliferation, EMT, colony formation, protection from apoptosis in MCF10A cells in vitro, and liver overgrowth in vivo, whereas overexpression of human YAP1-2α in the UMSCC-11A squamous cell carcinoma line increased cell death (See Finch-Edmondson, pg. 25, col. 1, 3rd paragraph). Finch-Edmondson et al. finds that whilst the difference in YAP function may be due to cellular context, it cannot be discounted that the specific YAP isoform utilized or the combination may contribute to this result (See Finch-Edmondson, pg. 25, col. 1, 3rd paragraph). Plus, Finch-Edmondson et al. teaches that other studies directly compared human YAP isoforms to draw conclusions about the functional importance of different YAP domains; for example, human YAP1-2α is a stronger co-activator than human YAP1-1β (See Finch-Edmondson, pg. 25, col. 1, 4th paragraph). Moreover, Finch-Edmondson et al. teaches that there is sufficient evidence indicating that YAP’s protein-protein interaction domains contribute significantly to its transcriptional activity (See Finch-Edmondson, pg. 25, col. 1, last paragraph). Multiple studies have shown that critical mutations within one or more WW domains affect YAP’s transcriptional activity, which may prevent YAP association with DNA-binding transcription factors or its interaction with other transcriptional modulators (See Finch-Edmondson, pg. 25, col. 1, last paragraph to col. 2, 1st paragraph). Other studies have shown that deletion of YAPs C-terminus decreased oncogenic functions, abolished EMT-like morphological changes induced by active YAP in MCF10A cells, and failure to induce cellular proliferation in the mouse retina in vivo (See Finch-Edmondson, pg. 25, col. 2, 1st paragraph). Whilst previous studies have postulated that the insertion of additional amino acids within the C-terminal TAD of YAP can impair its transcriptional activity, a comprehensive analysis of the relative transcriptional potency of C-terminal TAD variants has not yet been done (See Finch-Edmondson, pg. 25, col. 2, 2nd paragraph). Finch-Edmondson et al. examined the effects of C-terminal insertions where disruption to the leucine zipper and the WW domains play key roles in determining YAP transcriptional activity (See Finch-Edmondson, pg. 25, col. 2, 2nd paragraph). As such, Finch-Edmondson et al. demonstrates the unpredictability in making modifications to the protein sequence and/or nucleic acid encoding the protein sequence given that importance of several domains in the YAP’s function. Finch-Edmondson et al. even demonstrates that natural YAP isoforms exhibit different functions.
Additionally, Fujita et al. teaches a neuronal YAP isoform termed YAPdeltaC (See Fujita et al., Nature Comm. 8:1-15 (2017) at abstract). Fujita et al. teaches that YAP/YAPdeltaC interacts with RORalpha via the second WW domain and served as co-activators of its transcriptional activity (See Fujitia, abstract). YAP is involved in an atypical form of necrosis induced by alpha-amanitin, transcriptional repression-induced atypical cell death (TRIAD) in which C-terminal truncated isoforms of YAP (ins13, ins25, and ins61 possessing additional mini-exon sequences between exon 5 and exon 6) play critical roles (See Jujita, pg. 2, col. 2, 2nd paragraph). The researchers found that YAPdeltaC-ins61 had the strongest anti-TRIAD activity (See Jujita, pg. 2, col. 2, 2nd paragraph). Further, Fujita et al. found that overexpression of YAPdeltaC prevents TRIAD in Huntington’s disease in vitro models (See Jujita, pg. 2, col. 2, 2nd paragraph). Fujita et al. also found that YAP/YAPdeltaC functioned as a transcriptional co-activator of RORalpha, and rescued the spinocerebellar ataxia type 1 (SCA1) pathology and symptoms of adults (See Jujita, pg. 2, col. 2, 2nd paragraph). Thus, Jujita et al. teaches three specific mammalian YAP sequences. However, the prior art fails to either teach a core structure or sequence that is needed for a modified mammalian YAP or a polynucleotide encoding the modified mammalian YAP to exhibit the function of a native mammalian YAP in order to treat MCI, or teach a representative number of modified mammalian YAPs or polynucleotide encoding the modified mammalian YAP. Thus, the claims are directed to polypeptides and/or polynucleotides with a certain function but no correlated structure associated with that function. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches several examples of amino acid sequences as mammalian YAPs including SEQ ID NO: 1 (i.e., rat YAPΔC-ins61), SEQ ID NO: 3 (i.e., rat YAPΔC-ins13), SEQ ID NO: 4 (i.e., rat YAPΔC-ins25), SEQ ID NO: 5 (i.e., rat YAP), SEQ ID NO: 6 (i.e., mouse YAP), SEQ ID NO: 7 (i.e., human YAP2), SEQ ID NO: 8 (i.e., human YAP1-2 delta), SEQ ID NO: 9 (i.e., human YAP1-2 alpha), SEQ ID NO: 10 (i.e., human YAP1-2 beta), SEQ ID NO: 11 (i.e., human YAP1-2 gamma), SEQ ID NO: 12 (i.e., human YAP1), SEQ ID NO: 13 (i.e., human YAP1-1 gamma), SEQ ID NO: 14 (i.e., human YAP1-1 delta), SEQ ID NO: 15 (i.e., human YAP1-1 alpha), and SEQ ID NO: 16 (i.e., human YAP1-1 beta) (See instant, [0030]). As such, the instant specification teaches 3 specific modified YAP protein/nucleic acid sequences, i.e., SEQ ID NOs: 1 and 3-4, where the sequences have been truncated at the C-terminus and include an inserted mini-exon sequence between exon 5 and 6 (See Fujita, pg. 2, col. 2, 2nd paragraph). SEQ ID NOs: 5-16 represent naturally occurring YAP isoforms. The specification also teaches that the number of amino acid residues of the mammalian YAP is not particularly limited (See instant, [0031]). The amino acid residues of the mammalian YAP can also be modified by glycosylation, acetylation, phosphorylation, lipidation, stable isotope labeling or the like (See instant, [0031]). Plus, regarding the mammalian YAP polynucleotide sequence, the specification teaches that those skilled in the art can specifically and clearly understand a nucleotide sequence corresponding to the amino acid sequence thereof by referring to the amino acid sequence of the mammalian YAP and a codon table known in the art (See instant, [0032]). SEQ ID NO: 2 is an example of a polynucleotide sequence encoding SEQ ID NO: 1 (See instant, [0032]). Although the specification teaches 15 mammalian YAP amino acid sequences, i.e., SEQ ID NOs: 1 and 3-16, where three of these sequences are a combination of a fragment and variant with an inserted portion, and one polynucleotide sequence encoding one of the YAP amino acid sequences, i.e., SEQ ID NO: 1, given the breadth of the claimed mammalian YAP protein and polynucleotide sequences as discussed supra, the examples in the specification do not constitute a representative number of species within the claimed genus such that an ordinary skilled artisan would extend functionality to the full claimed genus. Similarly, the examples fail to indicate a shared core structure or sequence necessary for each species within the claimed genus to exhibit the function of a native YAP protein in order to treat MCI. Thus, the examples in the specification are not sufficient for the skilled artisan to envisage which structural manipulations of a native mammalian YAP protein would preserve function.
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, what 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 polypeptides which preserve the required function, 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. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 1-6 do not meet the written description requirement.
Claims 1 and 3-4 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. NOTE: this rejection is based on a substance.
Independent claim 1 includes a “substance capable of increasing an amount of mammalian YAP in a nucleus of a brain neuron”. As discussed in the “Claim Interpretation” section supra, the instant specification teaches that the mammalian YAP-enhancing substance is not particularly limited as long as the substance is capable of increasing an amount of mammalian YAP in a nucleus of a brain neuron by an action of promoting the translocation of the mammalian YAP into a brain neuron nucleus, action of enhancing the expression of the mammalian YAP in a brain neuron nucleus, or the like (e.g., a polypeptide such as an antibody, a polynucleotide, a saccharide, a lipid, an organic or inorganic compound) (See instant, [0044]). As such, the scope of the claimed substance recited in claim 1 encompasses any substance having any structure/sequence. As such, the claimed substance does not require a core structure or sequence necessary for each species within the claimed genus to exhibit the claimed function of increasing an amount of mammalian YAP in a nucleus of a brain neuron. Therefore, there is an enormous array of substances including proteins, polynucleotides, small molecules, lipids, carbohydrates, etc. without a required core structure or sequence necessary for the substance to increase an amount of mammalian YAP in a nucleus of a brain neuron.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Urfer-Buchwalder et al. US Publication No. 2023/0348978 A1 teaches that SLC2004 (sphingosylphosphorylcholine) and lysophosphatidylcholine are GPR4 agonists, which indirectly would increase expression of a gene such as YAP1 (See ‘978, [0065], [0067]). As such, these are two specific substances that would increase the expression of a mammalian YAP. Miller et al. teaches that serum-derived sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) as small molecule activators of YAP by inducing YAP nuclear localization through S1P2 receptor, Rho GTPase activation, and F-actin polymerization, independent of the core Hippo pathway kinases (See Miller et al., Chem & Biol. 19:955-962 (2012) at abstract). Thus, given the breadth of the claimed substance encompassing any structure/sequence, the prior art fails to either teach a core structure or sequence that is needed for a substance to increase an amount of mammalian YAP in a nucleus of a brain neuron. Thus, the claims are directed to substances with a certain function but no correlated structure associated with that function. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification broadly teaches that the substance is not limited and including a polypeptide such as an antibody, a polynucleotide, a saccharide, a lipid, an organic compound or an inorganic compound (See instant, [0044]). Examples include a lysophospholipid such as LPA, S1P, lysophosphatidylserine (LPS), lysophoshatidylinositol (LPI), and lysophosphatidylethanolamine (LPE), and a S1P receptor agonist such as KRP-203, CS-0777, ponesimod, and siponimod (See instant, [0044]). Although the specification teaches that a lysophospholipid and a S1P receptor agonist are examples of a substance that is capable of increasing an amount of mammalian YAP in a nucleus of a brain neuron, given the breadth of the claimed substance as discussed supra, the examples in the specification do not constitute a representative number of species within the claimed genus such that an ordinary skilled artisan would extend functionality to the full claimed genus. Similarly, the examples fail to indicate a shared core structure or sequence necessary for each species within the claimed genus to exhibit the function of increasing an amount of mammalian YAP in a nucleus of a brain neuron. Thus, the examples in the specification are not sufficient for the skilled artisan to envisage which substances would preserve function.
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, what 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 polypeptides which preserve the required function, 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. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 1 and 3-4 do not meet the written description requirement.
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 1-6 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 the prevention or treatment of mild cognitive impairment (MCI) by administering instant SEQ ID NO: 1, a polynucleotide encoding SEQ ID NO: 1, or a lysophospholipid or a S1P receptor agonist as a substance capable of increasing an amount of mammalian YAP in a nucleus of brain neuron to a subject in need of the treatment of MCI, but does not reasonably provide enablement for the prevention or treatment of mild cognitive impairment (MCI) by administering a mammalian YAP other than instant SEQ ID NO: 1, a polynucleotide encoding a mammalian YAP other than instant SEQ ID NO: 1, or a substance other than a lysophospholipid or a S1P receptor agonist to a subject in need of the treatment of MCI. 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.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The eight In re Wands factors are applied to Claims 1-6 as follows:
The Breadth of the Claims and The Nature of the Invention
Although addressing that the subject is suffering from MCI or at risk of suffering from MCI in claim 1 by administering a mammalian YAP, a polynucleotide encoding mammalian YAP, or a substance capable of increasing an amount of mammalian YAP in a nucleus of brain neuron (hereinafter referred to as “the substance”), there is no common core structure or sequence shared among the claimed species to suggest that an ordinary skilled artisan can extrapolate the efficacy of one sequence, i.e., instant SEQ ID NO: 1, and one substance, i.e., S1P, to non-structurally related sequences and/or substances. Notably, a mammalian YAP or polynucleotide encoding the mammalian YAP encompass a modified native YAP protein sequence or polynucleotide sequence with any number of substitutions, deletions or insertions, and a fragment sequence thereby including any dipeptide to a sequence with a single deleted residue at the N- and/or C-terminus. Moreover, a mammalian YAP that comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 1 encompasses a vast array sequences with up to 72 modifications including substitutions, deletions or insertions. Without a common core structure or sequence or a representative number of species, an ordinary skilled artisan would be unduly burdened to test each sequence and/or substance. Accordingly, claims 1-6 are unduly broad with respect to the administration of the encompassed agents to be administered.
The State of the Prior Art
Regarding the scope of mammalian YAPs and substances to be administered, as discussed in the first 112(a), written description rejection supra, Finch-Edmondson et al. teaches that YAP is a transcriptional co-activator that functions as an effector for the mammalian Hippo signaling pathway (See Finch-Edmondson et al., Biochem. Biophys. Rep. 6:24-31 (2016) at pg. 24, col. 1, 1st paragraph). YAP promotes growth and cell survival by regulating genes involved in proliferation, and interacts with many proteins via several protein-interaction domains to facilitate nuclear localization, DNA-binding and recruitment of transcription factors (See Finch-Edmondson, pg. 24, col. 1, 1st paragraph to col. 2, 1st paragraph). Finch-Edmondson et al. also teaches that there are at least eight alternatively spliced isoforms (See Finch-Edmondson, pg. 24, col. 2, 2nd paragraph) where these human isoforms exhibit different functions. For example, overexpression of human YAP1-2γ promoted cellular proliferation, EMT, colony formation, protection from apoptosis in MCF10A cells in vitro, and liver overgrowth in vivo, whereas overexpression of human YAP1-2α in the UMSCC-11A squamous cell carcinoma line increased cell death (See Finch-Edmondson, pg. 25, col. 1, 3rd paragraph). Finch-Edmondson et al. finds that whilst the difference in YAP function may be due to cellular context, it cannot be discounted that the specific YAP isoform utilized or the combination may contribute to this result (See Finch-Edmondson, pg. 25, col. 1, 3rd paragraph). Plus, Finch-Edmondson et al. teaches that other studies directly compared human YAP isoforms to draw conclusions about the functional importance of different YAP domains; for example, human YAP1-2α is a stronger co-activator than human YAP1-1β (See Finch-Edmondson, pg. 25, col. 1, 4th paragraph). Multiple studies have shown that critical mutations within one or more WW domains affect YAP’s transcriptional activity, which may prevent YAP association with DNA-binding transcription factors or its interaction with other transcriptional modulators (See Finch-Edmondson, pg. 25, col. 1, last paragraph to col. 2, 1st paragraph). Other studies have shown that deletion of YAPs C-terminus decreased oncogenic functions, abolished EMT-like morphological changes induced by active YAP in MCF10A cells, and failure to induce cellular proliferation in the mouse retina in vivo (See Finch-Edmondson, pg. 25, col. 2, 1st paragraph). Whilst previous studies have postulated that the insertion of additional amino acids within the C-terminal TAD of YAP can impair its transcriptional activity, a comprehensive analysis of the relative transcriptional potency of C-terminal TAD variants has not yet been done (See Finch-Edmondson, pg. 25, col. 2, 2nd paragraph). Finch-Edmondson et al. examined the effects of C-terminal insertions where disruption to the leucine zipper and the WW domains play key roles in determining YAP transcriptional activity (See Finch-Edmondson, pg. 25, col. 2, 2nd paragraph). As such, Finch-Edmondson et al. demonstrates the unpredictability in making modifications to the protein sequence and/or nucleic acid encoding the protein sequence given the importance of several domains in the YAP’s function. Finch-Edmondson et al. even demonstrates that natural YAP isoforms exhibit different functions, albeit, these different functions did not examine brain neuronal function.
Therefore, the level of predictability in the art is dependent on many factors including the functionality of a mammalian YAP, polynucleotide encoding the mammalian YAP or substance in brain neurons. Although, finding prevention and treatment for MCI is important, the state of the art requires vast amounts of data, including analysis of the efficacy of a representative number of mammalian YAPs, polynucleotides encoding the mammalian YAPs or substances on preventing or treating MCI, producing animal models based on said data, in vitro and in vivo experiments, and phase 0, I, II, III, and IV clinical trials.
The Level of Skill in the Art
Practitioners in this art (medical clinicians, pharmacists, doctors and/or pharmaceutical chemists) would presumably be highly skilled in the art for prevention and treatment of MCI in a subject by administering a mammalian YAP, polynucleotide encoding the mammalian YAP or substance to the subject
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable. If one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains (i.e., administering a mammalian YAP, polynucleotide encoding the mammalian YAP or substance to a subject suffering from or at risk of suffering from MCI in order to prevent or treat MCI), then there is a lack of predictability in the art. Moreover, it is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. The court has indicated that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species, what other species will work.
In the instant case, Applicants only demonstrate that S1P as a substance and instant SEQ ID NO: 1 can prevent or treat MCI development and/or progression (See instant, [0092]-[0100]). As discussed in the “Claim Interpretation” section supra, the specification discusses that high necrotic cell numbers were seen in MCI patients when compared to healthy control patients and AD patients, and examined the number of necrotic cells in brain neurons in two types of AD mouse models, i.e., 5xFAD mice and APP-KI mice) where the number of necrotic cells increased from 1 to 6 months of age whereas the number of necrotic cells decreased after 6 months of age (See instant, [0082], [0084], Figures 5A-C). As such, these results were interpreted such that around 6 months reflect the condition (symptoms) of MCI, before 6 months of age, i.e., at 1 month of age, reflects the condition before MCI development or at a very early stage after MCI development, and after 6 months of age reflect the condition (symptoms) of AD patients (See instant, [0085]). Moreover, the specification teaches that the expression of nuclear YAP was detected in the healthy patients whereas the amounts of nuclear YAP were decreased in the AD patients and further decreased in the MCI patients (See instant, [0088]; Figures 1 and 9A). Instead, it was found that YAP was cytoplasmically colocalized with amyloid beta in AD and MCI patient brain neurons (See instant, [0088]; Figure 8A). It is known that when LATS1 is phosphorylated at Ser909, it suppresses the nuclear translocation of YAP, which correlated with the finding that AD and MCI patients had higher pLATS1 levels when compared to the control patients (See instant, [0088]; Figure 8A and 9B). Furthermore, It is known that S1P suppresses the phosphorylation of LATS1 via the S1P receptor thereby necessarily resulting in YAP nuclear translocation, which in turn, suppresses Hippo-pathway dependent necrosis (See instant, [0091]). As such, S1P or instant SEQ ID NO: 1 was administered to 5xFAD mice at1 month of age (i.e., indicated supra as reflecting the condition before MCI development or at a very early stage after MCI development) (See instant, [0092]). As a result, the amount of nuclear YAP in brain neurons had been increased and/or restored to the levels of normal mice at 6 months of age (i.e., indicated supra as reflecting the condition (symptoms) of MCI) (See instant, [0092]; Figure 10). Figure 11C and D depict that S1P and SEQ ID NO: 1 administration reduced extracellular Aβ level in 5xFAD mice at 6 months of age (See instant, [0092]). Moreover, the administration of S1P or instant SEQ ID NO: 1 also significantly resolved ER dilation of 5xFAD mice at 1 month of age, significantly resolved ER stability of 5xFAD mice at 1 month of age, and restored ER to the state of normal mice (See instant, [0092]; Figures 12-15). pSer46-MARCKS levels, which are known to be elevated by HMGB1 released by necrotic cells, were decreased to the levels of normal mice at 6 months of age as depicted in Figure 16 (See instant, [0095]; Figure 16). Figure 17 depicts that S1P and SEQ ID NO: 1 administration improved cognitive functions based on score of alternation behavior back to normal levels (See instant, [0097], [0099]; Figure 17). Applicants appear to rely on the assumption that by providing evidence that S1P and instant SEQ ID NO: 1 resulted in positive results discussed supra in the 5xFAD AD mouse model would exhibit similar intended results for administering any mammalian YAP, any polynucleotide encoding the any mammalian YAP, or any substance. However, such an assumption cannot be made because there is no indication that an amino acid sequence, a polynucleotide sequence encoding the amino acid sequence, or a substance that differs structurally from S1P or instant SEQ ID NO: 1 would exhibit similar positive results. Nor does efficacy of S1P and instant SEQ ID NO: 1 constitute a representative number of species within the claimed genus that an ordinary skilled artisan can extrapolate from to extend to the full scope of the claimed genus. Since the Specification fails to demonstrate a core structure or sequence shared among the species with the claimed genus, there would be no way of determining without undue experimentation which mammalian YAPs other than instant SEQ ID NO: 1, polynucleotides encoding a mammalian YAP other than instant SEQ ID NO: 1, or substance other than a lysophospholipid or a S1P receptor agonist would exhibit such results. Therefore, without more experimentation demonstrating the efficacy of a representative number of amino acid sequences, polynucleotide sequences, or substances, the level of unpredictability remains high. Therefore, it is unpredictable that administering a mammalian YAP other than instant SEQ ID NO: 1, a polynucleotide encoding a mammalian YAP other than instant SEQ ID NO: 1, or a substance other than a lysophospholipid or a S1P receptor agonist to a subject in a similar fashion as that of S1P or instant SEQ ID NO: 1 because the claimed sequences do not share a common core structure or sequence that would be indicative of the desired result.
The Amount of Direction Provided by the Inventor,
The Presence or Absence of Working Examples, and
The Quantity of Experimentation Necessary
The specification does not enable any person skilled in the art to which it pertains (i.e. administering a mammalian YAP, polynucleotide encoding the mammalian YAP or substance to a subject suffering from or at risk of suffering from MCI in order to prevent or treat MCI) to make and/or use the invention commensurate in scope with the claims. There is a lack of adequate guidance from the specification or prior art with regard to the actual prevention or treatment of MCI by administering to a subject a mammalian YAP, polynucleotide encoding the mammalian YAP or substance. Applicants fail to provide the guidance and information required to ascertain where the claimed mammalian YAPs, polynucleotides encoding the mammalian YAPs or substances will be effective against preventing or treating MCI without resorting to undue experimentation. Applicant's limited disclosure is noted but is not sufficient to justify claiming all mammalian YAPs, polynucleotides encoding the mammalian YAPs or substances broadly.
Absent a reasonable a priori expectation of success for using a representative number of mammalian YAPs, polynucleotides encoding the mammalian YAPs or substances to prevent or treat MCI, one skilled in the art would have to extensively test YAP expression levels, ER function, phosphorylated factor levels, Aβ levels, and cognitive function levels in vitro and in vivo. Since each prospective embodiment, and indeed future embodiments as the art progresses, would have to be empirically tested, and those which initially failed tested further, an undue amount of experimentation would be required to practice the invention as it is claimed in its current scope, because the specification provides inadequate guidance to do otherwise.
The amount of direction or guidance presented in the specification is limited to S1P as a substance and instant SEQ ID NO: 1 as a mammalian YAP. As discussed in the “Claim Interpretation” section supra, the Specification discloses several working examples where S1P or instant SEQ ID NO: 1 were administered to 5xFAD mice and resulting in the prevention and treatment of MCI (See Specification, [0092]-[099]; Figures 5 and 9-17) (note: full discussion of the examples will not be reiterated but are incorporated as discussed supra). However, as noted in “Breadth of the Claims and Nature of the Invention" Section, the scope of a mammalian YAP, polynucleotide encoding the mammalian YAP or substance is enormous such that it includes fragments, modified protein or polynucleotide sequences, or any substance where these species do not share a common core structure or sequence. As such, the animal models used in the specification may not be indicative of valid results (i.e., preventing or treating MCI by administering any mammalian YAP other than instant SEQ ID NO: 1, any polynucleotide encoding a mammalian YAP other than instant SEQ ID NO: 1, or any substance other than a lysophospholipid or a S1P receptor agonist). Thus, since the Specification fails to provide a representative number of mammalian YAPs, polynucleotides encoding the mammalian YAPs or substances sharing a common core sequence or structure which would prevent or treat MCI in a subject, there would be no way of determining whether full scope of the claimed method is achievable without an undue quantity of experimentation.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
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).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to Claims 1-6, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the invention as claimed in Claims 1-6 would not be enabled by the written disclosure excluding that of preventing or treating MCI by administering instant SEQ ID NO: 1 as a mammalian YAP, a polynucleotide encoding instant SEQ ID NO: 1 or a lysophospholipid or a S1P receptor agonist to a subject in need thereof. Therefore, Claims 1-6, are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to administer any mammalian YAP other than instant SEQ ID NO: 1, any polynucleotide encoding a mammalian YAP other than instant SEQ ID NO: 1, or any substance other than a lysophospholipid or a S1P receptor agonist to a subject in order to prevent or treat MCI.
Claim Rejections - 35 USC § 102
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.
Claims 1-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tanaka et al., Nature Comm. 11:1-22 (January 2020) (cited in the IDS received on 6/7/22).
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
For claims 1-2, Tanaka et al. found that the frequency of necrosis reaches a peak during the preclinical stage of AD pathology in two types of AD mouse models by examining pSer46-MARCKS levels (See Tanaka, pg. 2, col. 2, last paragraph; pg. 11, col. 1, 4th paragraph). This showed that active necrosis is more abundant at the prodromal stage of MCI than the clinical stage of AD in human patients (See Tanaka, pg. 3, col. 2, last paragraph; pg. 11, col. 1, 4th paragraph; Fig. 2b, d and e). Such data correlates with the finding that there is elevated CSF-HMGB1 levels in human MCI (See Tanaka, pg. 4, col. 1, last paragraph; Fig. 1). As such, Tanaka et al. found that active necrosis, which leads to elevated CSF-HMGB1, occurs in a precursor stage of MCI. Tanaka et al. also found that neuronal cell death in the early stage of AD (i.e., during MCI) is Hippo pathway-dependent necrosis (See Tanaka, pg. 5, col. 2, last paragraph; pg. 7, col. 1, 2nd paragraph; pg. 11, col. 1, last paragraph). YAP is sequestered to cytoplasmic Aβ eventually impairing the function of YAP in the nucleus (See Tanaka, pg. 5, col. 2, last paragraph; pg. 7, col. 1, 2nd paragraph; pg. 11, col. 1, last paragraph; Fig. 5-8, 11). Plus, Tanaka et al. found that LATS1 kinase is activated in human cortical neurons of MCI, which prevents nuclear translocation of YAP (See Tanaka, pg. 6, col. 2, last paragraph; Fig. 9a, b). Thus, Tanaka et al. concludes that neuronal necrosis induced by YAP deprivation occurs most actively in the early stages of AD including preclinical AD, MCI or ultra-early stage of AD before extracellular Aβ aggregation (See Tanaka, pg. 13, col. 1, 3rd paragraph). Restoration of the YAP protein level using an AAV vector encoding YAPΔC-ins61 (i.e., 100% identical to instant SEQ ID NO: 1) successfully inhibited necrosis during the early stage of AD (i.e., during MCI) thereby efficiently preventing cognitive impairment (i.e., MCI) and extracellular Aβ aggregation in AD model mice when administered to the mice at 1 month of age (See Tanaka, pg. 8, col. 1, 1st paragraph to pg. 9, col. 1, 2nd paragraph; pg. 11, col. 2, last paragraph; pg. 18, col. 2, 2nd paragraph; Figs. 9a-h). In coming to this conclusion, Tanaka et al. administered S1P into 5xFAD mice (i.e., an AD mouse model) via continuous intrathecally at either 1 or 5 months of age and continued until 6 months or AAV-YAPΔC-ins61 as a one-shot injection into 5xFAD mice (i.e., an AD mouse model) at 1 or 5 months of age where imaging was performed two days after injection (See Tanaka, pg. 8, col. 1, 1st paragraph to pg. 9, col. 1, 2nd paragraph; pg. 18, col. 2, 3rd paragraph; Fig. 9a-h). Therefore, the disclosure of Tanaka et al. satisfies the claim limitations with respect to administering a polynucleotide encoding a mammalian YAP comprising an amino acid sequence having 100% identity to instant SEQ ID NO: 1 or S1P as a substance capable of increasing an amount of mammalian YAP in a nucleus of a brain neuron to a subject in order to prevent or treat MCI as recited in instant claims 1-2.
For claims 3-6, with respect to where the MCI is a condition having an elevated concentration of HMGB1 in cerebrospinal fluid, Tanaka et al. discloses that the current definition of MCI is largely based on subjective complaints by patients who have insufficient cognitive decline to be diagnosed with dementia and who remain adequately socially adjusted (See Tanaka, pg. 13, col. 1, 2nd paragraph). No objective markers are available to support the subjective diagnosis or to evaluate the pathological state during MCI stage (See Tanaka, pg. 13, col. 1, 2nd paragraph). As such, Tanaka et al. examined HMGB1 levels in CSF of human MCI patients, healthy patients, and AD patients (See Tanaka, pg. 2, col. 1, last paragraph). CSF samples were collected from 34 normal controls, 14 disease controls, 26 MCI patients and 73 AD patients (See Tanaka, pg. 2, col. 1, last paragraph). Tanaka et al. found that CSF-HMGB1 level was significantly elevated in the clinically diagnosed MCI group, but not the AD group, relative to the normal or disease controls or relative to the AD group (See Tanaka, pg. 2, col. 2, 2nd paragraph; Fig. 1a). Therefore, Tanaka et al. concludes that in combination with amyloid PET to quantify the extracellular Aβ burden and the use of CSF-HMGB1 to detect the amount of on-going cell death could serve as a sensitive quantitative marker for evaluating disease progression (See Tanaka, pg. 13, col. 1, 2nd paragraph). Thus, CSF-HMGB1 is a powerful tool for evaluating the activity of cell death in such stages (See Tanaka, pg. 13, col. 1, 3rd paragraph). Thus, Tanaka et al. demonstrates that MCI is a condition having an elevated concentration of HMGB1 in CSF as compared with a control subject without MCI where the control subject is a healthy individual or an AD patient as recited in instant claims 3-6.
Accordingly, Tanaka’s disclosure anticipates instant claims 1-6.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Fujita et al., Nat. Commun. 8:1-15 (2017) in view of Lin et al., Oncotarget 8:24088-24098 (2017).
For claims 1-2, Fujita et al. teaches that spinocerebellar ataxia type 1 (SCA1) is a neurological disease caused by the gene, ataxin-1 (Atxn1), and can affect cerebral neurons leading to cognitive impairment in patients with SCA1 (See Fujita, p. 2, col. 1, 1st paragraph). Fujita et al. postulated that SCA may be a developmental disorder that affects cerebellar neurons during embryogenesis or in early childhood (See Fujita, p. 2, col. 1, 2nd paragraph). One study showed that Atxn1 indirectly interacts with RORα, an orphan nuclear receptor in the developmental molecular biology of SCA1 (See Fujita, p. 2, col. 1, last paragraph). This was confirmed by decreased RORα levels with expression of mutant Atxn1 protein thereby broadly affecting expression of target genes necessary for cerebellar development (See Fujita, p. 2, col. 2, 1st paragraph). Fujita et al. also teaches that the transcriptional co-factor YAP is involved in an atypical form of necrosis induced by alpha-amanitin, transcriptional repression-induced atypical cell death (TRIAD) in which C-terminal truncated isoforms of YAP (ins13, ins25 and ins61 possessing additional mini-exon sequences between exon 5 and exon 6) (note: 100% identity to instant SEQ ID NO: 1) play critical roles (See Fujita, p. 2, col. 2, 2nd paragraph). Fujita et al. found that YAPΔC-ins61 had the strongest anti-TRIAD activity of the three isoforms when expressed in developing Drosophilia that were fed alpha-amanitin (See Fujita, p. 2, col. 2, 2nd paragraph). As such, in light of these previous studies, Fujita et al. tested the therapeutic effect of YAPΔC-ins61 on SCA1 pathology using a newly developed Tet-ON YAPΔC-ins61 system in Atxn1-KI (SCA1154Q/2Q) mice such that the transgenic mice expressed YAPΔC-ins61(See Fujita, p. 2, col. 2, last paragraph; pg. 3, col. 1, last paragraph to col. 2, 1st paragraph). The researchers found that YAP/YAPΔC-ins61 functioned as a transcriptional co-activator of RORα thereby markedly rescuing the pathology and symptoms in adulthood (See Fujita, p. 2, col. 2, last paragraph to pg. 3, col. 1, 1st paragraph). Supplementation of YAP/YAPΔC-ins61 overcame the toxic effect of mutant Atxn1 and restored the transcriptional activity of RORα (See Fujita, p. 3, col. 1, 1st paragraph). Thus, Fujita et al. demonstrates that administration of a mammalian YAP comprising an amino acid sequence having 100% identity to instant SEQ ID NO: 1 functions as a transcriptional co-activator of RORα.
However, Fujita et al. does not expressly teach that such administration would prevent or treat MCI in a subject.
Lin et al. discusses animal studies that have indicated associations between circadian clock genes and cognitive impairment (See Lin, abstract). In mammals, the molecular clock mechanism is presently viewed as a complicated interplay of transcriptional feedback regulatory loops involving various circadian clock genes that control and support circadian rhythms (See Lin, pg. 24089, col. 1, 1st paragraph). Lin et al. assessed whether 11 circadian clock genes are associated with cognitive aging in an old Taiwanese population (See Lin, abstract; pg. 24089, col. 2, 1st and 3rd paragraph). The patients of the study population had a median MMSE score of 27, i.e., a range of 25-29 (See Lin, pg. 24089, col. 2, 2nd paragraph; Table 1). As discussed in the “Claim Interpretation” section supra, the instant specification defines MCI as a condition that has decline in cognitive function where “decline in cognitive function” means a MMSE score between 19-27. As such, the patients evaluated in Lin’s study encompass the claimed patient population as recited in instant claim 1. Lin et al. found that associations between cognitive aging and SNPs in 4 key circadian clock genes: CLOCK, NPAS2, RORα, and RORβ (See Lin, abstract; pg. 24089, col. 2, 4th paragraph). They also found interactions between CLOCK, NPAS2, RORα, and RORβ affected cognitive aging (See Lin, abstract; pg. 24089, col. 2, last paragraph; Table 3). Table 5 demonstrates a summarized model of the associations between the MMSE scores and SNPs within the 4 key circadian clock genes (See Lin, abstract; pg. 24090, col. 1, 3rd paragraph; Table 5). In particular, Lin et al. found that 42 SNPs in the RORα gene may contribute to susceptibility of cognitive aging (See Lin, abstract; pg. 24090, col. 1, last paragraph). Thus, Lin et al. suggests a correlation between SNPs in the RORα gene thereby resulting in RORα gene dysfunction and MCI.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Fujita et al. and administer YAPΔC-ins61 as a mammalian YAP comprising an amino acid sequence having 100% identity to instant SEQ ID NO: 1 to a subject in order to treat MCI instead of SCA1 given that YAPΔC-ins61 functions as a transcriptional co-activator of RORα and given that SNPs in the RORα gene are associated with MCI. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because 42 SNPs in the RORα gene thereby resulting in RORα gene dysfunction were known to be associated with MMSE scores of MCI patients and may contribute to susceptibility of cognitive aging as taught by Lin et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the YAPΔC-ins61 of Fujita et al. was administered to patients to treat SCA1 by functioning as a transcriptional co-activator of RORα and thereby administering YAPΔC-ins61 to MCI patients instead of SCA1 patients would support the treatment of MCI by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Fujita et al., Nat. Commun. 8:1-15 (2017) in view of Lin et al., Oncotarget 8:24088-24098 (2017), as applied to claims 1-2 above, and further in view of Festoff et al., J. Neuroinflammation 13:12 pages (2016), as applied to claims 3-6 herewith.
For claims 1-2, please see discussion of Fujita et al. and Lin et al. supra.
For claims 3-6, in light of the combined teachings of Fujita et al. and Lin et al. an ordinary skilled artisan would be motivated with a reasonable expectation of success to administer YAPΔC-ins61 to a subject in order to treat MCI given that YAPΔC-ins61 was known to function as a transcriptional co-activator of RORα, and SNPs in the RORα gene thereby resulting in RORα dysfunction were known to be associated with MMSE scores in MCI patients.
However, Fujita et al. and Lin et al. do not expressly teach that the MCI isa condition having an elevated concentration of HMGB1 in CSF as compared with a control subject without MCI such as a healthy patient or an AD patient.
Festoff et al. teaches that HMGB1 and thrombin are key molecules of two most potent host defense systems that converse on the innate immune system, coagulation and inflammation (See Festoff, pg. 2, col. 1, last paragraph). Since both are proinflammatory and known to disrupt vascular barriers in other tissues, Festoff et al. sought to examine the role they may play in BBB disruption (See Festoff, pg. 2, col. 1, last paragraph to col. 2, 1st paragraph). To do so, Festoff et al. first measured HMGB1 levels in MCI, AD and normal aged subjects (See Festoff, pg. 2, col. 2, 2nd paragraph; pg. 4, col. 1, last paragraph). Festoff et al. found that there was a significant increase in serum HMGB1 and soluble receptor for advanced glycation end products (sRAGE) that correlated well with Aβ levels in AD patients when compared to control subjects (See Festoff, abstract; pg. 4, col. 1, last paragraph; Figure 1). Moreover, Festoff et al. found that serum HMGB1 levels were significantly elevated in MCI patients compared to controls or AD patients (See Festoff, abstract). Thus, Festoff et al. concludes that HMGB1 and/or sRAGE in addition to Aβ could have a potential use as prognostic/diagnostic markers for AD and MCI (See Festoff, pg. 4, col. 2, 1st paragraph). Therefore, Festoff et al. demonstrates that patients suffering from MCI have an elevated concentration of HMGB1 in serum as compared to a control subject such as a healthy subject or an AD subject.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Fujita et al. and administer YAPΔC-ins61 as a mammalian YAP comprising an amino acid sequence having 100% identity to instant SEQ ID NO: 1 to a subject in order to treat MCI exhibiting an elevated concentration of HMGB1 in serum as compared to a control subject without MCI such as a healthy subject or an AD subject instead of SCA1 given that YAPΔC-ins61 functions as a transcriptional co-activator of RORα and given that SNPs in the RORα gene are associated with MCI, and given that MCI patients had a significant increase in serum HMGB1 levels as compared to a control subject without MCI such as a healthy subject or an AD subject. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because 42 SNPs in the RORα gene thereby resulting in RORα gene dysfunction were known to be associated with MMSE scores of MCI patients and may contribute to susceptibility of cognitive aging as taught by Lin et al.; and because MCI patients were known to have an elevated concentration of HMGB1 in serum as compared to a control subject without MCI such as a healthy subject or an AD subject as taught by Festoff et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the YAPΔC-ins61 of Fujita et al. was administered to patients to treat SCA1 by functioning as a transcriptional co-activator of RORα and thereby administering YAPΔC-ins61 to MCI patients exhibiting an elevated concentration of HMGB1 in serum as compared to a control subject without MCI such as a healthy subject or an AD subject instead of SCA1 patients would support the treatment of MCI by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Additionally and/or alternatively, with respect to where the HMGB1 concentration is elevated in CSF, it is noted that the scope of claims 3 and 5 only limit the MCI and do not correlate the administration of the mammalian YAP to the elevated HMGB1 concentration. Therefore, since the combination of Fujita et al., Lin et al., and Festoff et al. suggest administer YAPΔC-ins61 to a MCI patient exhibiting an elevated concentration of HMGB1 in serum as compared to a control patient without MCI such as a healthy patient or an AD patient as discussed supra, it would necessarily follow that HMGB1 concentration in CSF is also elevated. In other words, the MCI being a condition having an elevated concentration of HMGB1 in CSF as compared to a control subject such as a healthy subject or an AD subject constitutes a property of the MCI that would necessarily be present. The claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654