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.
Please note that the Species A is hereby withdrawn after further consideration.
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. The amendment received on June 11, 2026, amended claims 1-3.
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. Receipt is also acknowledged of the English language translation for Japanese Application No. 2019-145259.
Sequence Interpretation
For claim 1, please note that the Examiner is interpreting the scope as open-ended requiring at least 90% 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 1 encompasses up to 36 modifications including substitutions, deletions and/or insertions. Thus, a polynucleotide that encodes this sequence encompasses polynucleotides that encode any sequence with up to 36 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” where the substance is a lysophospholipid or a S1P receptor agonist, it is noted that the combination of the prior art and the instant specification demonstrate that an ordinary skilled artisan would put Applicants in possession of a representative number of substances where the substances are a lysophospholipid or a S1P receptor agonist. 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). With respect to the instant specification, 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]). As such, given the species taught in the instant specification and combined with the pre-existing knowledge in the art regarding the genetic code and its redundancies, an ordinary skilled artisan would have put one in possession of the genus of substances being a lysophospholipid or a S1P receptor agonist given that a representative number of species are known. Thus, an ordinary skilled artisan would conclude that the applicant was in possession of the claimed genus of substances before the effective filing date of the instant application.
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 at 1 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.
Response to Arguments
Applicant’s arguments, see Response, filed June 11, 2026, with respect to the claim objections have been fully considered and are persuasive. The objections of claims 1-3 and 5 have been withdrawn.
Applicant’s arguments, see Response, filed June 11, 2026, with respect to the 112(a), written description, rejection have been fully considered and are persuasive. The rejection of claims 1 and 3-4 as failing to comply with the written description requirement has been withdrawn. Please note that this written description rejection pertained to the substance.
Applicant’s arguments, see Response, filed June 11, 2026, with respect to the 102(a)(1) rejection have been fully considered and are persuasive. The rejection of claims 1-6 as being anticipated by Tanaka et al., Nature Comm. 11:1-22 (January 2020) (cited in the IDS received on 6/7/22) has been withdrawn.
Applicant’s arguments, see Response, filed June 11, 2026, with respect to the 103(a) rejection have been fully considered and are persuasive. The rejection of claims 1-2 as being unpatentable over Fujita et al., Nat. Commun. 8:1-15 (2017) in view of Lin et al., Oncotarget 8:24088-24098 (2017) has been withdrawn.
Applicant’s arguments, see Response, filed June 11, 2026, with respect to the 103(a) rejection have been fully considered and are persuasive. The rejection of claims 1-6 as being unpatentable over Fujita et al., Nat. Commun. 8:1-15 (2017) in view of Lin et al., Oncotarget 8:24088-24098 (2017), and further in view of Festoff et al., J. Neuroinflammation 13:12 pages (2016) has been withdrawn.
Maintained/Modified Rejections in light of Applicants’ Amendments
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. Also please note that the rejection has been updated in light of Applicants’ amendments to claims 1-2.
Independent claim 1 includes a “mammalian YAP or a polynucleotide encoding mammalian YAP” where the mammalian YAP is a polypeptide comprising an amino acid sequence having at least 90% 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 36 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. 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 a large 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 binding 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 the 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. Moreover, when comparing SEQ ID NO: 1 with these other sequences, only SEQ ID NOs: 3-4 are at least 90% identical. 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.
Response to Arguments
Applicant's arguments filed 6/11/26 for claims 1-6 have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s argument, i.e., the amendment overcomes the written description rejection since the amendment limits the mammalian YAP to a polypeptide and the skilled artisan will understand that any variant of YAP having the same activity as SEQ ID NO: 1 (i.e., a polypeptide having at least 90% identity to SEQ ID NO: 1 and having transcriptional activity) will have the same activity when treating MCI (See Applicant’s Response received on 6/11/26, pg. 6), it is found unpersuasive. Pursuant to MPEP §2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Additionally, the importance of structure/function correlations was highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centorcor Biologics, App. No. 2013-1338, -1346 (Fed. Cir. , July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, Abbvie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity. Moreover, the ’128 and ’485 patents do not describe any common structural features of the claimed antibodies. The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.”
In the instant case, it is noted that instant SEQ ID NO: 1 is a variant and fragment of a natural mammalian YAP protein. As stated in the rejection supra, the specification and prior art (i.e., Fujita et al.) teach 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). The researchers found that YAPdeltaC-ins61 (i.e., instant SEQ ID NO: 1) had the strongest anti-TRIAD activity (See Jujita, pg. 2, col. 2, 2nd paragraph). As such, the prior art and instant specification combined only teaches 3 specific species that fall within the claimed polypeptide genus. The scope of the claimed polypeptide encompasses modifications of SEQ ID NO: 1 that already is a variant and fragment of a natural YAP protein. Although the three known species are acknowledged, the Examiner maintains that a determination of a core structure, sequence, or residues that would be necessary in order for a polypeptide as claimed to function as SEQ ID NO: 1 in order to treat MCI in a subject, is not apparent, especially given that SEQ ID NO: 1 is a variant and fragment of a natural mammalian YAP protein. Without such a determination, it would be difficult for a skilled artisan to envision the correlation between structure and function for the whole genus and/or to predict what would be covered by the functionally claimed genera because Applicants have failed to provide a representative number of species to support the scope of the whole genus.
Furthermore, as discussed in the rejection supra and pursuant to MPEP 2163.05(I)(B), [t]he written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.)
In the instant case, although there are situations where a single species adequately supports a genus (See MPEP 2163.05(I)(B), e.g., In re Rasmussen, 650 F.2d 1212, 1214, 211 USPQ 323, 326-27 (CCPA 1981) (disclosure of a single method of adheringly applying one layer to another was sufficient to support a generic claim to "adheringly applying" because one skilled in the art reading the specification would understand that it is unimportant how the layers are adhered, so long as they are adhered), given that there are only three specific species (i.e., SEQ ID NOs: 1 and 3-4) that exhibit the function of a mammalian YAP, the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the three disclosed. Therefore, even if the instant specification is deemed to support possession of a limited number of polypeptide species, Applicants have not demonstrated a representative number of species within the claimed genus of any polypeptide that has up to 36 modifications relative to SEQ ID NO: 1 to constitute possession of the claimed genus.
Accordingly, the rejection of claims 1-6 is maintained as Applicant’s argument is found unpersuasive.
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 and 3-6 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 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 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. Please note that the rejection has been updated in light of Applicants’ amendments; namely, with respect to the substance. The rejection remains pending with respect to the mammalian YAP polypeptide, but the substance is fully enabled. Since the substance is fully enabled, discussion will be limited to the mammalian YAP polypeptide.
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 and 3-6 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 that is a polypeptide having at least 90% identity to SEQ ID NO: 1 or a polynucleotide encoding mammalian YAP, there is no common core structure or sequence shared among the species within the scope of the claimed genus to suggest that an ordinary skilled artisan can extrapolate the efficacy of one sequence, i.e., instant SEQ ID NO: 1 to sequences with up to 36 amino acid modifications. Notably, a mammalian YAP or polynucleotide encoding the mammalian YAP encompasses a polypeptide having at least 90% identity to SEQ ID NO: 1 encompasses a vast array sequences with up to 36 modifications including substitutions, deletions or insertions. Furthermore, it is noted that SEQ ID NO: 1 is known as YAPdeltaC-ins61, which has been truncated at the C-terminus (i.e., a fragment) and has an inserted mini-exon sequence between exon 5 and 6 (i.e., variant) (See Fujita, pg. 2, col. 2, 2nd paragraph). As such, the claimed mammalian YAP polypeptide encompasses further fragments and variants of an already fragment/variant of a natural mammalian YAP protein. Thus, 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. Accordingly, claims 1 and 3-6 are unduly broad with respect to the administration of the encompassed to be mammalian YAP.
The State of the Prior Art
Regarding the scope of mammalian YAPs 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 and polynucleotide encoding the mammalian YAP 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, and polynucleotides encoding the mammalian YAPs 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 or polynucleotide encoding the mammalian YAP 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 or polynucleotide encoding the mammalian YAP 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 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). As such, instant SEQ ID NO: 1 was administered to 5xFAD mice at 1 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 SEQ ID NO: 1 administration reduced extracellular Aβ level in 5xFAD mice at 6 months of age (See instant, [0092]). Moreover, the administration of 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 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 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 polypeptide that has at least 90% identity to SEQ ID NO: 1, or any polynucleotide encoding the polypeptide. However, such an assumption cannot be made because there is no indication that a polypeptide or a polynucleotide sequence encoding the polypeptide that differs structurally from instant SEQ ID NO: 1 would exhibit similar positive results. Nor does efficacy of instant SEQ ID NO: 1 constitute a representative number of species within the claimed genus of polypeptides 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 or polynucleotides encoding a mammalian YAP other than instant SEQ ID NO: 1 would exhibit such results. Therefore, without more experimentation demonstrating the efficacy of a representative number of polypeptides or polynucleotide sequences, the level of unpredictability remains high. Therefore, it is unpredictable that administering a mammalian YAP other than instant SEQ ID NO: 1 or a polynucleotide encoding a mammalian YAP other than instant SEQ ID NO: 1 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 or polynucleotide encoding the mammalian YAP 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 that is a polypeptide having at least 90% identity to SEQ ID NO: 1 or a polynucleotide encoding the mammalian YAP. Applicants fail to provide the guidance and information required to ascertain where the claimed mammalian YAPs or polynucleotides encoding the mammalian YAPs except for SEQ ID NO: 1 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 polypeptides that are at least 90% identical to SEQ ID NO: 1 or polynucleotides encoding the polypeptides broadly.
Absent a reasonable a priori expectation of success for using a representative number of mammalian YAPs or polynucleotides encoding the mammalian YAPs 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 instant SEQ ID NO: 1 as a mammalian YAP. As discussed in the “Claim Interpretation” section supra, the Specification discloses several working examples where instant SEQ ID NO: 1 was 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 or a polynucleotide encoding the mammalian YAP is large such that it includes fragments, modified protein or polynucleotide sequences that are at least 90% identical to SEQ ID NO: 1, 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 or any polynucleotide encoding a mammalian YAP other than instant SEQ ID NO: 1). Thus, since the Specification fails to provide a representative number of mammalian YAPs that are a polypeptide having at least 90% identity to SEQ ID NO: 1 or polynucleotides encoding the mammalian YAPs 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 and 3-6, 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 and 3-6 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 or a polynucleotide encoding instant SEQ ID NO: 1 to a subject in need thereof. Therefore, Claims 1 and 3-6, 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 or any polynucleotide encoding a mammalian YAP other than instant SEQ ID NO: 1 to a subject in order to prevent or treat MCI.
Response to Arguments
Applicant's arguments filed 6/11/26 for claims 1 and 3-6 with respect to the mammalian YAPs have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s argument, i.e., the amendment overcomes the scope of enablement rejection since the amendment limits the mammalian YAP to a polypeptide having at least 90% identity to SEQ ID NO: 1 and having YAP transcriptional activity (See Applicant’s Response received on 6/11/26, pg. 7), it is found unpersuasive. Pursuant to MPEP 2164.01(a), “[t]he determination that “undue experimentation” would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. 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’.” In re Wands, 858 F.2d at 737, 8 USPQ2d at 1400, 1404.
MPEP 2164.02 states “[t]o make a valid rejection, one must evaluate all the facts and evidence and state why one would not expect to be able to extrapolate that one example across the entire scope of the claims. For a claimed genus, representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art (in view of level of skill, state of the art and the information in the specification) would expect the claimed genus could be used in that manner without undue experimentation. Proof of enablement will be required for other members of the claimed genus only where adequate reasons are advanced by the examiner to establish that a person skilled in the art could not use the genus as a whole without undue experimentation.” (emphasis added).
In the instant case, as discussed in the rejection supra, the instant specification provides evidence of a single species, i.e., SEQ ID NO: 1, as a mammalian YAP that treats and/or prevents MCI in a subject. Although the amended scope of claim 1 with respect to the mammalian YAP is acknowledged, i.e., limited to polypeptides having at least 90% identity to SEQ ID NO: 1, given the limited representative examples of polypeptides demonstrating efficacy, the Examiner maintains that an ordinary skilled artisan would be required to undergo undue experimentation in order to practice the scope of the claimed method. This is because an ordinary skilled artisan would be unable to extrapolate the positive data of SEQ ID NO: 1 to extend to the scope of the claimed genus of polypeptides.
Additionally, the Office’s position is supported by the holding in Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362, 52 USPQ2d 1129 (Fed. Cir. 1999). As discussed in MPEP 2164.06(b)(I)(A), in Enzo Biochem, Inc. v. Calgene, Inc., the court held that two patents with claims directed to genetic antisense technology (which aims to control gene expression in a particular organism), were invalid because the breadth of enablement was not commensurate in scope with the claims. Both specifications disclosed applying antisense technology in regulating three E. coli genes. Despite the limited disclosures, the specifications asserted that the "[t]he practices of this invention are generally applicable with respect to any organism containing genetic material which is capable of being expressed … such as bacteria, yeast, and other cellular organisms." Thus, the court construed the claims to encompass the application of antisense methodology in a broad range of organisms. Ultimately, the court relied on the fact that (1) the amount of direction presented and the number of working examples provided in the specification were very narrow compared to the wide breadth of the claims at issue, (2) antisense gene technology was highly unpredictable, and (3) the amount of experimentation required to adapt the practice of creating antisense DNA from E. coli to other types of cells was quite high, especially in light of the record, which included notable examples of the inventor’s own failures to control the expression of other genes in E. coli and other types of cells. Thus, the teachings set forth in the specification provided no more than a "plan" or "invitation" for those of skill in the art to experiment using the technology in other types of cells.
In the instant case, like in the Calgene case, the amount of direction and the number of working examples provided in the specification were very narrow compared to the wide breadth of the claims at issue, treating or preventing MCI is a highly unpredictable technology, and the amount of experimentation required to adapt the practice of treating or preventing MCI by administering a polypeptide having at least 90% identity to SEQ ID NO: 1 or a polynucleotide encoding the polypeptide is quite high, given limited data provided in the art and in the instant specification. Therefore, like in the Calgene case, the teachings set forth in the specification and in the prior art provide no more than a "plan" or "invitation" for those of skill in the art to experiment using the technology for polypeptides and polynucleotides encoding the polypeptides that do not have a common core structure, sequence and/or amino acid residues with SEQ ID NO:1. Applicants are invited to provide additional data demonstrating a representative number of polypeptides and/or polynucleotides encoding the polypeptides that function as claimed. Without such additional data, the instant disclosure and the state of the art fail enable one or ordinary skill in the art to perform the claimed method without undue experimentation.
Accordingly, the rejection of claims 1 and 3-6 is maintained.
Examiner Comment
Notwithstanding the 112(a) rejections supra, the scope of the claimed invention is free of the prior art. The closest prior art is Okazawa US Patent No. 7,951,928 B2 issued on May 31, 2011, and Fujita et al., Nat. Commun. 8:1-15 (2017) (cited in the Action mailed on 2/23/26). Okazawa teaches a preventive/remedy for a neurodegenerative disease such as polyglutamine diseases, and Alzheimer’s disease by administering a protein of any one of SEQ ID NOs: 1-3 (See Okazawa, col. 2, 4th paragraph). When comparing Okazawa’s SEQ ID NOs: 1-3 to instant SEQ ID NO: 1, there is at least 90% identity between Okazawa’s SEQ ID NOs: 1-2 and instant SEQ ID NO: 1, and 100% identity between Okazawa’s SEQ ID NO: 3 and instant SEQ ID NO: 1. However, Okazawa does not teach or suggest that one of SEQ ID NOs: 1-3 can treat or prevent MCI. Plus there is no indication of a correlation between mild neuronal cell death found by Okazawa, which was termed “omega process” (See Okazawa, col. 3, 4th paragraph) and MCI. Furthermore, 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 (See Fujita, p. 2, col. 1, 1st to 2nd paragraph; p. 2, col. 2, 1st paragraph). However, Fujita et al. does not teach or suggest a correlation between RORalpha and MCI, or teach/suggest treating or preventing MCI. Therefore, the claimed invention is free of the prior art.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THEA D' AMBROSIO whose telephone number is (571)270-1216. The examiner can normally be reached M-F 11:00 to 8:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached at 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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