Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of Application/Election/Restrictions
Applicant’s election without traverse of Group I (claims 16-30), residues Leu, Ile, Val and Phe for species of hydrophobic residues, SEQ ID NO:8 for species of synthetic peptide, Parkinson’s disease for species of disease, G51D for species of point mutation in the reply filed on October 14, 2025 is acknowledged.
Claims 1-15 are canceled. Claims 16-35 are pending in this application. Claims 31-35 are withdrawn without traverse (filed 10/14/2025) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Upon reconsideration, the species election among different point mutations is withdrawn because the subject matter can be found in the same prior art reference. The subject matter to the extent of different point mutations recited in claim 30 is included and under examination in this office action. Election was made without traverse in the reply filed on October 14, 2025.
Claims 16-30 are under examination with respect to Leu, Ile, Val and Phe for hydrophobic residues, SEQ ID NO:8 for synthetic peptide, Parkinson’s disease for disease, A30P, G51D for a point mutation in this office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
5. Claim 16 is objected to because of the following informalities: the recitation “AGADIR” is not a unique or common abbreviation in the art. Applicants are required to spell out “AGADIR” at the first usage. Appropriate correction is required.
Claim Rejections - 35 USC § 112
6. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 16-30 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 16-30 are indefinite because:
i. Claims 16-30are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: No subject for the step of administering recited in independent claim 16. The subject is required for the claimed method but is not recited or included for the step of administering, which renders the claimed indefinite.
ii. The term “AGADIR” is recited in the claims without providing a full name for the abbreviated name. Without identification of property or combination of properties which are unique to and, therefore, definitive of the instant recitations, the metes and bounds of the claims remain undetermined. Further, the use of laboratory designations only to identify a particular database renders the claims indefinite because different laboratories may use the same laboratory designations to define completely distinct databases.
The claims and the specification depend on the descriptions, data and algorithms of “AGADIR” to define the databases and structures of the inhibitors encompassed by the claims, but since the data and algorithms in the “AGADIR” can be updated, the specification fails to define the claimed data and algorithms, and therefore the claims include any number of undefined data and algorithms, and their variants since its initial database. It is unclear what data and algorithms, the initial or the updated, should be used in the claimed method. Thus, the claims are indefinite.
ii. Claim 19 recites the limitation "the picomolar" in line 1 of the claim. There is insufficient antecedent basis for this limitation in the claim.
iii. Claim 23 recites the limitation "the decrease in the level of …. " in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
iv. Claim 30 recites the limitation "the gene… f …. " in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
v. The rest of the claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
7. 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 16-30 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as based on a disclosure which is not enabling. The disclosure does not enable one of ordinary skill in the art to practice the invention without the subject for the step of administering, which is/are critical or essential to the practice of the invention but not included in the claim(s). See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976). There is no subject recited for the step of administering in the method recited independent claim 16. However, the subject is required for the claimed method and the step of administering. The claimed method is not enabling without the subject for the step of administering.
8. Claims 16-30 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for inhibiting in vitro a-synuclein aggregation by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 as determined by dual-color FCCS (dcFCCS) and single molecule Forster resonance energy transfer (smFRET), or reducing generation of reactive oxygen species (ROS) induced by a-synuclein toxic oligomers (a-S oligomers) in a-S oligomers-treated human SH-SY5Y neuroblastma cells in vitro by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 compared to a-S oligomers-treated human SH-SY5Y neuroblastma cells without treatment in vitro, does not reasonably provide enablement for a method of treatment or prophylaxis of a syncleinopathy in a subject in need thereof in vivo using the claimed synthetic peptide inhibitor having a structure defined by the features recited in claim 16 as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. In addition, the specification does not enable the invention of claims 16-30 that is directed to a method of prevention and curing.
“There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is ‘undue’. These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)”. See MPEP § 2164.01.
Claims 16-30 are drawn to a method of treatment or prophylaxis of a synucleinopathy in a subject in need thereof, administering to the subject an effective dose of a synthetic peptide inhibitor of a-synuclein aggregation, wherein the synthetic peptide inhibitor of a-synuclein aggregation (i.e. a-synuclein inhibitory peptide) has a structure defined by the features of (i)-(v) and activities of inhibiting (a) in vitro a-synuclein aggregation at a molar ratio of 1:1~1:15 and (b) cellular toxicity associated with a-synuclein toxic oligomers and (c) exhibits higher affinity to a-synuclein toxic oligomers than to monomeric a-synuclein as determined by dsFCCs and/or smFRET recited in claim 16.
The claims encompass methods of treating and preventing all forms of synucleinopathy including PD and epilepsy caused by all possible mechanisms using structurally and functionally undefined a-synuclein inhibitory peptides, including at least 84% sequence identity to an amino acid sequence selected from PSMa3 (SEQ ID NO:2), All-Leu (SEQ ID NO:4), All-Leu-19 (SEQ ID NO:5), Scaffold-19 (SEQ ID NO:6) and LL-37 (SEQ ID NO:8).
The instant invention is based on findings that i) inhibiting in vitro a-synuclein aggregation by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 as determined by dual-color FCCS (dcFCCS) and single molecule Forster resonance energy transfer (smFRET); ii) reducing generation of reactive oxygen species (ROS) induced by a-synuclein toxic oligomers (a-S oligomers) in a-S oligomers-treated human SH-SY5Y neuroblastma cells in vitro by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 compared to a-S oligomers-treated human SH-SY5Y neuroblastma cells without treatment in vitro.
Applicant extrapolates the above findings to the claimed method of treatment or prophylaxis of a synucleinopathy in a subject in need thereof comprising administering to the subject an effective dose of a synthetic peptide inhibitor of a-synuclein aggregation (a-synuclein inhibitory peptide), wherein the a-synuclein inhibitory peptide has a length between 15-50 consecutive amino acids and a structure defined by the features (i)-(v) and activities of (a)-(c) recited in independent claim 16.
First, Applicant is not enabled for a method of preventing or treating including preventing a person from getting all forms of synucleinopathy including PD, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, Lewy body variant of Alzheimer’s disease (AD) and neurodegeneration with brain iron accumulation. The instant claims recite the limitation “treatment or prophylaxis of a synucleinopathy….…", which encompasses preventing and curing all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD….in view of paragraphs [paragraphs [0062] and [0063] of instant specification (based on published application).
[0062] Administration of an inhibitor of the present disclosure, can prevent and/or delay the onset or the progression of the formation of a-synuclein deposits in a mammalian subject, e.g. a mammal known or suspected to have or being at risk of developing a synucleinopathy.
[0063] The treatment of a synucleinopathy as described herein can comprise one or more of the following: reducing or ameliorating the severity and/or duration of the synucleinopathy or one or more symptoms thereof, preventing the advancement of the synucleinopathy, causing regression of the synucleinopathy, preventing or delaying the recurrence, development, onset or progression of the synucleinopathy or ….., a treatment of a synucleinopathy as described herein may be a prophylactic treatment, e.g. in a subject at risk of developing a synucleinopathy. Prophylaxis or a prophylactic treatment of a synucleinopathy as described herein can include one or more of the following: preventing or delaying the onset of the synucleinopathy or one or more symptoms thereof, enhancing or improving the prophylactic effect of another therapy (e.g., another prophylactic drug) against the synucleinopathy.
However, neither the specification nor the prior art provides guidance as to how to prevent a person from having all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms or cure all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms. Any individual has a potential to develop any form of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms. Applicant fails to teach how to identify or predict when and which person among us would be susceptible to such a disease or developing the disease, and predict when the person would need administration of the claimed a-synuclein inhibitory peptide to prevent the disease. Neither the specification nor the prior art teaches that administration of the claimed a-synuclein inhibitory peptide can prevent a person from getting any form of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms or cure any form of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms.
The cause of the disease can be due to a genetic mutation, which is a natural process. The causes of different forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms are different. As admitted by Applicant, “different a-synuclein species (monomers, non-toxic oligomers, toxic oligomers, and fibrils) have different biophysical and structural features which apparently have distinct implications in the pathogenesis of a-synucleinopathies” (see [0015] of the instant specification). For example, Moore et al. teach that the pathogenesis of PD can be familial and associated with different gene deficits including a-synuclein, parkin, PINK1, LRRK, NR4A2 etc. (see p. 59-71, Moore et al., Annu. Rev. Neurosci. 2005; 28:57-87), due to oxidative stress resulting production of ROS and mitochondrial dysfunction or could be due impairment of ubiquitin-proteasome system (see p. 72-74, in particular). If the cause is due to genetic deficits or mutations, it is impossible to prevent a person from getting or developing different forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms because the gene mutation or gene deficiency is a natural process result. The specification fails to provide sufficient guidance as to enable one of skill in the art to practice the invention as it pertains to a method of prevention or curing. Further, Applicant also fails to provide specific guidance as to what specific amount of the claimed fusion polypeptide can be used and thus would be effective to prevent or cure all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms. Thus, a skilled artisan cannot contemplate a right amount to prevent the disease or to prevent a person from getting the disease.
Second, based on the specification and the prior art, Applicant is enabled for inhibiting a-synuclein aggregation in vitro by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 as determined by dcFCCS and smFRET. Applicant is also enabled for reducing generation of reactive oxygen species (ROS) induced by a-synuclein toxic oligomers (a-S oligomers) in a-S oligomers-treated human SH-SY5Y neuroblastma cells in vitro by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 compared to a-S oligomers-treated human SH-SY5Y neuroblastma cells without treatment in vitro.
The claims are not limited to the methods set forth above but also encompass treatment or prophylaxis of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms. However, the specification fails to provide sufficient guidance to enable one of skill in the art to practice the full scope of the claimed invention without undue experiments because of the complexity and unpredictability of the diseases and failure to provide support a correlation between the in-vitro cellular models and the pathogeneses or causes of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms in vivo in view of Moore et al. (see p. 59-71, Moore et al., Annu. Rev. Neurosci. 2005; 28:57-87), Falkenburger et al. (see p. 261, summary, Falkenburger et al., J. Neural. Transm, 2006; 70:261-268), Tayebati (see p. 106, 1st col, 2nd paragraph, Tayebati, Mech. Ageing Dev. 2006. 127: 100-8) and Sarter (see p. 645, abstract, Sarter, Neurosci. and Biobehav. Rev. 2004. 28: 645-650).
While the skill level in the art is high, the level of predictability is low. Based on Applicant’s own admission in [0014] of the specification, “different a-synuclein species (monomers, non-toxic oligomers, toxic oligomers, and fibrils) have different biophysical and structural features which apparently have distinct implications in the pathogenesis of a-synucleinopathies”. The in vitro cellular model of a-S oligomers-treated human SH-SY5Y neuroblastma cells only reflects reducing generation of ROS induced by a-S oligomers in the a-S oligomers-treated human SH-SY5Y neuroblastma cells in vitro by the a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 compared to a-S oligomers-treated human SH-SY5Y neuroblastma cells with no treatment in vitro.
The specification provides no well-establish structural and functional relationship or correlation between inhibiting a-synuclein aggregation in vitro by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 as determined by dcFCCS and smFRET and treatment and prophylaxis of all forms of synucleinopathy using the claimed a-synuclein inhibitory peptide in vivo.
The specification provides no well-establish structural and functional relationship or correlation between reducing generation of ROS induced by a-synuclein toxic oligomers (a-S oligomers) in a-S oligomers-treated human SH-SY5Y neuroblastma cells in vitro by the a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 compared to a-S oligomers-treated human SH-SY5Y neuroblastma cells with no treatment in vitro and treatment and prophylaxis of all forms of synucleinopathy using the claimed a-synuclein inhibitory peptide in vivo.
Applicant obviously intended to treat all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD…caused by all possible mechanisms by using the claimed a-synuclein inhibitory peptide. However, the specification fails to provide a well-established correlation among different forms of synucleinopathy or PD or AD caused by different mechanisms. The specification fails to establish that different forms of synucleinopathy or PD or AD caused by different mechanisms can be treated by the same drugs or same conditions or have the same effects in response to the same drugs. Thus, it is unpredictable whether one treatment for one specific disorder can be applied to another disorder, indicating undue experimentation is required by a skilled artisan while practice the claimed invention.
Each type of animal models of synucleinopathy or PD or AD only reflects part of pathogenesis of the disease as taught by Moore et al. (see p. 59-71), Jagmag et al., (Front. Neurosci. 2016; 9:503. Doi:10.3389/fnins.2015.00503), Potashikin et al. (Parkinson’s Disease, 2011; 658083; doi:104061/2011/658083), Falkenburger et al. (see p. 261, summary), Tayebati (see p. 106, 1st col, 2nd paragraph) and Sarter (see p. 645, abstract). Jagmag et al. teach that while several models of PD have been created and used for evaluation of drugs on PD or pathogeneses of PD, none of the currently available models of PD completely reflect the PD in humans (see p. 1. Jagmag et al., Front. Neurosci. 2016; 9:503. Doi:10.3389/fnins.2015.00503). Potashkin et al. teach that current animal models do not replicate the true pathophysiology occurring in idiopathic PD and thus the results from animal models often do not translate to the clinic (see p.1, abstract; Potashikin et al., Parkinson’s Disease, 2011; 658083; doi:104061/2011/658083). For example, while toxin model induced by 6-OHDA, can reproduce behavioral deficits of PD, the effect of 6-OHDA does not mimic the progressive loss seen in PD (see p. 3, in particular). Jagmag et al. teach a combination of toxin-based animal models with genetic models can provide a better tool to evaluate all the symptoms of PD (see p. 7).
In this case, while the specification disclosed reduction of ROS induced by a-S oligomers in the a-S oligomers-treated human SH-SY5Y neuroblastma cells by the a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) in vitro compared to a-S oligomers-treated human SH-SY5Y neuroblastma cells with no treatment, the in vitro cellular models induced by a-S oligomers in SH-SY5Y neuroblastm cell cultures require additional animal models or other different models to verify the effects as taught by Falkenburger et al. (see p. 261, summary).
In addition, the presence of Lewy bodies (LB) in neurons is the hallmark of PD, the specification fails to teach the relationship between LB in PD and the reduction of ROS- or toxicity induced by a-S oligomers in the human SH-SY5Y neuroblastma cells by PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) or the claimed a-synuclein inhibitory peptide. Thus, it is unpredictable whether the claimed PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) or the claimed a-synuclein inhibitory peptide can be used for treatment or prophylaxis of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms.
The specification fails to provide sufficient guidance or evidence to demonstrate that all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms can be treated or prevented by the claimed a-synuclein inhibitory peptide including PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) because there is no well-established correlation between reduction of ROS or toxicity induced by a-S oligomers in the human SH-SY5Y neuroblastma cells by the claimed PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) and pathogeneses or causes of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms. In addition, Falkenburger et al. teaches that the results derived from cellular models induced by a-S oligomers or 6-OHDA or NMDA in neuronal cultures require additional animal models or other different models to verify the effects (see p.261, summary Falkenburger et al., J. Neural. Transm, 2006; 70:261-268). Since the pathogenesis of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms is complex and the causes of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms have not been fully understood and are equally complex, it is unpredictable whether the reduction of ROS or toxicity induced by a-S oligomers in the human SH-SY5Y neuroblastma cells by the claimed PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) in vitro can be applied to all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms or whether administration of the claimed a-synuclein inhibitory peptide or PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) can treat all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms, indicating that undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
Further, the specification fails to provide sufficient guidance as to what other a-synuclein inhibitory peptides or variants with at least 84% identity to recited SEQ ID NOs: including SEQ ID NO:8 are, and whether all a-synuclein inhibitory peptides or variants can be used in the claimed method because a single amino acid change on a molecule or protein can abolish the binding ability or activity of the molecule or the protein. For example, a substitution of lysine residue by glutamic acid at position 118 of acidic fibroblast growth factor results in a substantial loss of its biological activity including the binding ability to heparin and its receptor (Burgess et al. J of Cell Bio. 1990, 111:2129-2138). Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would not immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active because conformation is dependent upon surrounding residues; i.e. substitution of non-essential residues can often destroy activity. In addition to a core determinant sequence, the protein-protein interaction also relies on the flanking or noncontiguous residues (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452). The optimal binding motif for a domain is not necessarily suitable for physiological or in vivo interaction. The predictive data always need to be validated by actual analyses in cells (see p. 445, the third column, second paragraph, Pawson et al. 2003, Science 300:445-452). Alaoui-lsmaili teaches that designing a mutein having predictable activities is difficult because of the complexity of the interactions between ligands and receptors (Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507). For example, given the complexity of BMP-BMP receptor interactions, it is difficult to design BMPs with improved affinity and/or specificity for one specific receptor. More importantly, predicting the in vivo biological activity of such altered BMPs remains a challenging undertaking (see p. 502, right col., 2th paragraph). Further, when multiple mutations are introduced, there is even less predictability because Guo et al. teaches that the effects of mutations on protein function are largely additive (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210). The specification fails to teach what other structures/amino acid sequences can or cannot be included/changed in all a-synuclein inhibitory peptides recited in claim 16 in order to preserve the activity of PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) in reducing ROS or toxicity induced by a-S oligomers in the human SH-SY5Y neuroblastma cells in vitro as compared to no treatment, or even in treatment or prophylaxis of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms, indicating undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
A patent is granted for a completed invention, not the general suggestion of an idea and how that idea might be developed into the claimed invention. In the decision of Genentec, Inc, v. Novo Nordisk, 42 USPQ 2d 100,(CAFC 1997), the court held 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” and that “[t]ossing out the mere germ of an idea does not constitute enabling disclosure”. The court further stated that “when there is no disclosure of any specific starting material or of any of the conditions under which a process is to be carried out, undue experimentation is required; there is a failure to meet the enablement requirements that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art”, “[i]t is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement”.
The instant specification is not enabling because one cannot follow the guidance presented therein and practice the claimed method without first making a substantial inventive contribution.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, no working examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by one of skill in the art to perform in order to practice the full scope of the claimed invention as it pertains to a method of treatment or prophylaxis of a synucleinopathy by the claimed a-synuclein inhibitory peptides recited in claim 16.
Claim Rejections - 35 USC § 112
9. Claims 16-30 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.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claims 16-30 encompass using a genus of synthetic peptide inhibitor of a-synuclein aggregation (i.e. a-synuclein inhibitory peptide) for treating or preventing a genus of synucleinopathy in a subject in need thereof.
Claim 21 encompass using a genus of variants with at least 84% identity to recited SEQ ID NOs: including SEQ ID NO:8 for treating or preventing a genus of synucleinopathy in a subject in need thereof.
Applicant has not disclosed sufficient species for using the broad genus of a-synuclein inhibitory peptide or variants with at least 84% identity to recited SEQ ID NOs: including SEQ ID NO:8 for treating or preventing a genus of synucleinopathy.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. The specification only describes inhibiting a-synuclein aggregation in vitro by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 as determined by dcFCCS and smFRET and reducing generation of reactive oxygen species (ROS) induced by a-synuclein toxic oligomers (a-S oligomers) in a-S oligomers-treated human SH-SY5Y neuroblastma cells in vitro by a a-synuclein inhibitory peptide, PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) at a ratio of 1:1 for a-S oligomers to PSMa3 or LL-37 compared to a-S oligomers-treated human SH-SY5Y neuroblastma cells without treatment in vitro.
However, the claims are not limited to the method and PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) set forth above but also encompass using a genus of a-synuclein inhibitory peptide or variants of recited SEQ ID NO: including SEQ ID NO:8 for treating or preventing a genus of synucleinopathy in vivo. The specification provides no well-established structural and functional relationship or correlation between reducing ROS or toxicity induced by a-S oligomers in the human SH-SY5Y neuroblastma cells in vitro by PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) as compared to no treatment and the treatment or prophylaxis of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms by the claimed genus of a-synuclein inhibitory peptide having the features recited in claim 16.
The specification provides no identification of any particular portion of the structure that must be conserved for the claimed genus of a-synuclein inhibitory peptide or variants of recited SEQ ID NO: including SEQ ID NO:8. The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of a-synuclein inhibitory peptide having the features recited in claim 16 or the genus of variants with at least 84% identity to recited SEQ ID NO: including SEQ ID NO:8. There is no description of the conserved regions which are critical to the function of the claimed genus. The specification provides no description of the sites at which variability may be tolerated and there is no information regarding the relation of the structure of other a-synuclein inhibitory peptides having the features recited in claim 16 or variants with at least 84% identity to recited SEQ ID NO:8 to the function of PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) in reducing ROS or toxicity induced by a-S oligomers in the human SH-SY5Y neuroblastma cells in vitro as compared to no treatment, or even in treatment or prophylaxis of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms. Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to isolate and identify what other other a-synuclein inhibitory peptides having the features recited in claim 16 might be.
The specification provides no well-established correlation between in vitro cellular model of ROS or toxicity induced by a-S oligomers in the human SH-SY5Y neuroblastma cells in vitro and the pathogeneses of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms. The specification provides no information to demonstrate that all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms can be treated or prevented by the claimed a-synuclein inhibitory peptide including PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) because there is no well-established correlation between reduction of ROS or toxicity induced by a-S oligomers in the human SH-SY5Y neuroblastma cells by the claimed PSMa3 (SEQ ID NO:2) or LL-37 (SEQ ID NO:8) and treatment or prophylaxis of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms by the claimed genus of a-synuclein inhibitory peptide
Since the common characteristics/features of other a-synuclein inhibitory peptides or variants, and the pathogeneses and treatment of all forms of synucleoinopathy including PD, dementia with Lewy bodies, Lewy body variant of AD caused by all possible mechanisms are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of a-synuclein inhibitory peptides and the genus of synucleinopathy.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of a-synuclein inhibitory peptides and synucleiniopathy, 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, a method for treatment or prophylaxis of a synucleinopathy in a subject in need thereof by administration of a a-synuclein inhibitory peptide to the subject has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
10. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
11. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 16-28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hillman (WO2009/010968, published Jan 22, 2009, priority Jul 15, 2007).
Hillman (WO2009/010968) teach a method of treating different diseases including neurological diseases including Parkinson’s disease, Alzheimer’s disease ([000205]; [000408]; [000478]), comprising administering to a subject in need thereof (see para.[00049]-[00054]) a LL-37/hCAP18 peptide comprising the amino acid sequence of SEQ ID NO: 11, which is 94.6% identical to instant SEQ ID NO:8 (LL-37) (see the sequence alignment below; paras. [0009], [00013]; [00049]; [00059]; [000183]; [000205]; [000408]; [000478]), which meet the limitations recited in claims 16-28.
The LL-37 peptide disclosed by Hillman is 94.6% identical to instant SEQ ID NO:8 (LL-37) and have the properties and features recited in claims 16-27. The Parkinson’s disease is a synucleinopathy as recited in claims 1 and 28. Thus, Claims 16-28 are anticipated by Hillman (WO2009/010968).
The sequence search results disclose as follows:
SEQ ID NO:8
AVA92027
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
ID AVA92027 standard; protein; 40 AA.
XX
AC AVA92027;
XX
DT 19-MAR-2009 (first entry)
XX
DE Human Cathelicidin antimicrobial peptide (CAMP) sequence, SEQ: 11.
XX
KW Cathelicidin antimicrobial peptide; CAMP; therapeutic; protein therapy;
KW acne vulgaris; acquired immune deficiency syndrome; addisons disease;
KW alopecia; alzheimers disease; analgesic; angina; ankylosing spondylitis;
KW anorectic; antiallergic; antianginal; antiarrhythmic;
KW antiarteriosclerotic; antiarthritic; antiasthmatic; antibacterial;
KW antidiabetic; antiinfertility; antiinflammatory; antilipemic;
KW antimicrobial-gen.; antiparasitic; antiparkinsonian; antipsoriatic;
KW antiseborrheic; antiulcer; arthritis; arthrogryposis multiplex congenita;
KW asthma; atherosclerosis; atopic dermatitis; atrophy; auditory;
KW autoimmune disease; bacterial infection; blepharitis; bone disease;
KW bone tumor; bullous skin disease; cardiant; cardiovascular disease;
KW cardiovascular-gen.; carpal tunnel syndrome; celiac disease;
KW cerebroprotective; cerebrovascular ischemia; cholesteatoma; chondroma;
KW chronic obstructive pulmonary disease; cluster headache;
KW connective tissue disease; craniosynostosis; crohns disease;
KW cushings disease; cytostatic; dermatitis; dermatological;
KW dermatological disease; dermatomyositis; diabetes mellitus;
KW diabetic nephropathy; diabetic retinopathy; drug eruption; dysplasia;
KW ear disease; eating disorder; eating-disorders-gen.; encephalitis;
KW enchondromatosis; endocrine disease; endocrine-gen.; fibromyalgia;
KW folliculitis; fungal infection; fungicide; gallstones; gastritis;
KW gastrointestinal ulcer; gastrointestinal-gen.; giant bone cell tumor;
KW gout; graves disease; growth-disorder-gen.; guillain barre syndrome;
KW gynecological; hashimotos disease; headache; heart arrhythmia;
KW hematological-gen.; hyperglycemia; hypertension; hypoglycemia;
KW hypotensive; ileitis; immunomodulator; immunostimulant;
KW immunosuppressive; infectious arthritis; infertility;
KW inflammatory bowel disease; inflammatory disease;
KW inflammatory renal disease; insulin dependent diabetes;
KW insulin resistance; intestine disease; joint disease; kawasaki disease;
KW keratolytic; lambert-eaton syndrome; lichen; lipid metabolism disorder;
KW male osteoporosis; melanoma; metabolic-gen.; migraine;
KW motor neurone disease; multiple sclerosis; muscular-gen.;
KW musculoskeletal disease; musculoskeletal-gen.; myasthenia gravis;
KW mycobacterium tuberculosis infection; myocardial infarction; myositis;
KW myxedema; nephrotropic; neurodegenerative disease; neurological disease;
KW neuropathy; neuroprotective; nootropic; non-insulin dependent diabetes;
KW nutrition-disorder-gen.; obesity; ocular disease; ophthalmological;
KW optic neuritis; oral-dental-gen.; osteoarthritis;
KW osteogenesis imperfecta; osteomalacia; osteomyelitis; osteopathic;
KW osteopetrosis; ovary disease; pancreas disease; parapsoriasis;
KW parasitic infection; parkinsons disease; periodontitis;
KW pityriasis capitis infection; plasmodium falciparum infection;
KW polychondritis; polycystic ovary disease; primary sclerosing cholangitis;
KW prostate hyperplasia; prostatitis; protozoacide; protozoal infection;
KW pyelonephritis; reiter syndrome; respiratory-gen.; rheumatoid arthritis;
KW scleroderma; sepsis; sjoegrens syndrome; skin allergy; skin tumor;
KW sleep disorder; squamous cell carcinoma; stiff person syndrome;
KW sydenham chorea; syndrome x; tendinitis; thyroid disease; thyroiditis;
KW thyrotoxicosis; tourette syndrome; tuberculostatic; ulcerative colitis;
KW urinary tract infection; uropathic; vasotropic; viral infection;
KW virucide; vulnerary; wegener granulomatosis; weight gain; wound healing.
XX
OS Homo sapiens.
XX
CC PN WO2009010968-A2.
XX
CC PD 22-JAN-2009.
XX
CC PF 15-JUL-2008; 2008WO-IL000977.
XX
PR 15-JUL-2007; 2007IL-00184611.
PR 26-NOV-2007; 2007IL-00187627.
XX
CC PA (HILL/) HILLMAN Y.
XX
CC PI Hillman Y;
XX
DR WPI; 2009-E03937/14.
XX
CC PT Pharmaceutical composition useful for treating e.g. arthritis, multiple
CC PT sclerosis, obesity, and inflammatory disease comprises a compound which
CC PT is mammalian cathelicidin or active modified form of the cathelicidin,
CC PT and excipient or carrier.
XX
CC PS Claim 23; SEQ ID NO 11; 105pp; English.
XX
CC The present invention relates to a novel method for the treatment of
CC disease and promotion of healing. The method includes providing a
CC therapeutically effective amount of a mammalian antimicrobial peptide
CC (AMP) or analog thereof. In particular, the antimicrobial peptide is a
CC cathelicidin, its fragment or its analog. The invention is useful for the
CC preparation of a medicament for the treatment of a medical condition
CC selected from arthritis, multiple sclerosis, psoriasis, obesity, excess
CC weight, insulin resistance, osteoporosis, diabetes, inflammatory bowel
CC disease, Crohn's disease, ulcerative colitis, chronic obstructive
CC pulmonary disease, wound, rheumatoid arthritis, pyogenic arthritis, mixed
CC connective tissue disease, cholesteatoma, relapsing polychondritis,
CC autoimmune myositis, primary Sjogren's syndrome, smooth muscle autoimmune
CC disease, myositis, tendinitis, ligament inflammation, chondritis, joint
CC inflammation, synovial inflammation, carpal tunnel syndrome,
CC osteoarthritis, ankylosing spondylitis, skeletal inflammation, autoimmune
CC ear disease, fibromyalgia, periodontitis, autoimmune disease of inner
CC ear, pyelonephritis, other inflammatory renal disease such as diabetic
CC nephropathy and urinary tract infections, chronic autoimmune gastritis,
CC autoimmune atrophic gastritis, primary sclerosing cholangitis, autoimmune
CC achlorhydra, ileitis, chronic inflammatory intestinal disease, celiac
CC disease, eating disorder, gallstones, gastrointestinal ulcer,
CC neurodegenerative disease, Alzheimer's disease, Parkinson's disease,
CC myasthenia gravis, motor neuropathy, Guillain-Barre syndrome, autoimmune
CC neuropathy, Lambert-Eaton myasthenic syndrome, paraneoplastic
CC neurological disease, paraneoplastic cerebellar atrophy, non-
CC paraneoplastic stiff man syndrome, progressive cerebellar atrophy,
CC Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydeham chorea,
CC Gilles de Ia Tourette syndrome, autoimmune polyendocrinopathy, dysimmune
CC neuropathy, acquired neuromyotonia, arthrogryposis multiplex, optic
CC neuritis, spongiform encephalopathy, migraine, headache, cluster
CC headache, allergic dermatitis, dandruff, pemphigus vulgaris, lichen
CC planus, atopic dermatitis, scleroderma, dermatomyositis, alopecia,
CC blepharitis, skin carcinoma, melanoma, excema, squamous cell carcinoma,
CC acne vulgaris, erythema toxicum neonatorum, folliculitis, skin wrinkles,
CC autoimmune bullous skin disease, bullous pemphigoid, pemphigus foliaceus,
CC dermatitis, drug eruption, type I diabetes, type II diabetes, type B
CC insulin resistance, Schmidt's syndrome, Cushing's syndrome,
CC thyrotoxicosis, benign prostatic hyperplasia, pancreatic disease,
CC Hashimoto's thyroiditis, idiopathic adrenal atrophy, Graves' disease,
CC androgenic alopecia, thyroid disease, thyroiditis, spontaneous autoimmune
CC thyroiditis, idiopathic myxedema, ovarian autoimmunity, autoimmune anti-
CC sperm infertility, autoimmune prostatitis, Addison's disease, Type I
CC autoimmune polyglandular syndrome, Diabetes mellitus, hyperglycemia or
CC hypoglycemia, complications of diabetes and diabetes-related eye,
CC periodontitis, Osteomyelitis, bone cancer, Osteogenesis imperfecta,
CC Paget's disease, Osteochondroma, Osteomalacia, Osteomyelitis,
CC Osteopetroses, Renal Osteodystrophy, Unicameral Bone Spurs, Bone Tumor,
CC Craniosynostosis, Enchondroma, Fibrous Dysplasia, Giant Cell Tumor of
CC Bone, Infectious Arthritis, Osteomyelitis, Klippel-Feil Syndrome, Limb
CC Length Discrepancy, Osteochondritis Dissecans, bone loss in
CC periodontitis. The medical condition is a disease associated with
CC inflammation or a pathological inflammatory condition. The disease
CC associated with inflammation is selected from autoimmune inflammatory
CC disease, metabolic inflammatory disease, cutaneous inflammatory disease,
CC low level inflammatory disease, gastrointestinal inflammatory disease,
CC inflammatory bone condition, and respiratory inflammatory disease. Also
CC useful for promotion of wound healing. Also useful for treating gout,
CC Wegener's granulomatosis, Kawasaki's disease, Metabolic syndrome,
CC atherosclerosis, cardiovascular diseases, Angina, Arrhythmia, stroke,
CC hypertension, myocardial infarction, polycystic ovarian syndrome,
CC dyslipidemia, inflammatory eye disease, Reiter's syndrome, fungal
CC infection, viral disease, bacterial disease, parasitic disease, malaria,
CC tuberculosis, sepsis, protozoan disease, acquired immunodeficiency
CC syndrome, asthma, and sleepiness. The present sequence is an amino acid
CC sequence of a human Cathelicidin antimicrobial pro-peptide sequence used
CC in the present invention.
XX
SQ Sequence 40 AA;
Query Match 94.6%; Score 176; Length 40;
Best Local Similarity 94.6%;
Matches 35; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 1 LLGDFFRKSKEKIGKGFKRIVQRLKDFLRNLVPRTES 37
||||||||||||||| |||||||:|||||||||||||
Db 4 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES 40
Claim Rejections - 35 USC § 103
12. 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 of this title, 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 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Hillman (WO2009/010968) in view of Tsigelny et al. (ACS Chem. Neurosci. 2015; 6:403-416. DOI:10.1021/cn500332w).
Hillman (WO2009/010968) is set forth above but does not teach that Parkinson’s disease is a familial synucleinopathy and the subject presents a point mutation including A53T, A30P, E46K, G51D and/or H50Q recited in claims 29-30.
Tsigelny et al. teach that Parkinson’s disease (PD) includes familial PD, and familial forms of PD are caused by point mutations including A53T, A30P, E46K, G51D and H50Q in a-synuclein-encoding gene “SNCA” as in claims 29-30 (see p. abstract; p. 4492, 1st col., 2nd paragraph).
A person of ordinary skill in the art would have recognized that selecting and applying the patients with familial PD and presenting known point mutations A53T, A30P, E46K, G51D and/or H50Q and the known technique disclosed by Tsigelny to the Hillman’s method would have yielded the predictable result of treating PD and familial PD having point mutations of A53T, A30P, E46K, G51D and/or H50Q, and resulted in an improved method.
Selecting and including patients with familial PD having point mutations of A53T, A30P, E46K, G51D and/or H50Q in the Hillman’s method would treat patients with familial PD and expand application of the Hillman’s method, and would increase patient’s satisfaction with treatment of PD using LL-37 peptide because Hillman teaches a method of treating PD with the LL-37 peptide, PD includes familial PD, and patients with familial PD have point mutations including A53T, A30P, E46K, G51D and/or H50Q in a-synuclein-encoding gene “SNCA” and identified in patients having a familial PD.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the patients with familial PD with the known point mutations including A53T, A30P, E46K, G51D and/or H50Q and the known technique disclosed by Tsigelny to the Hillman’s method and yield the predictable result of treating PD including familial PD which presents point mutations including A53T, A30P, E46K, G51D and/or H50Q.
Conclusion
13. NO CLAIM IS ALLOWED.
14. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
CN101081864 teach a human recombinant LL-37 antibacterial peptide rLL-37-3 comprisng the amino acid sequence of SEQ ID NO:4, which is 95.7% identical to instant SEQ ID NO:8 (see the sequence alignment below).
SEQ ID NO:8
ARP18897
ID ARP18897 standard; peptide; 37 AA.
XX
AC ARP18897;
XX
DT 12-JUN-2008 (first entry)
XX
DE Human recombinant LL-37 antibacterial peptide rLL-37-3, SEQ ID 4.
XX
KW rLL-37; recombinant protein; protein production; genetic engineering;
KW protein therapy; therapeutic; bacterial infection; antibacterial;
KW viral infection; virucide; fungal infection; fungicide; hemolysis.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN CN101081864-A.
XX
CC PD 05-DEC-2007.
XX
CC PF 11-JAN-2007; 2007CN-10078120.
XX
PR 11-JAN-2007; 2007CN-10078120.
XX
CC PA (UYTH-) UNIV THIRD MILITARY MEDICAL CHINESE PEOP.
XX
CC PI Ge X;
XX
DR WPI; 2008-F02281/35.
XX
CC PT New rebuilt antibacterial peptides, useful for treating infection caused
CC PT by Gram-positive bacteria, Gram-negative bacteria, fungi or virus.
XX
CC PS Example 1; SEQ ID NO 4; 49pp; Chinese.
XX
CC The present invention relates to a novel group of antibacterial peptides
CC comprising recombinant rLL-37 antibacterial peptide. Independent claims
CC are included for: a loading protein sequence with negative charge for
CC preparing the recombinant rLL-37 peptide antibacterial peptide, where the
CC gene sequence encoding the loading protein has a sequence comprising 84
CC bp and the loading protein has a sequence comprising 28 amino acids; and
CC a method for preparing antibacterial peptide. The antibacterial peptide
CC is a recombinant 37 antibacterial peptide selected from rLL-37-1 to rLL-
CC 37-17. The antibacterial peptide can also be: a recombinant 24
CC antibacterial peptide selected from rLL-24-1 to rLL-24-8, a recombinant
CC 18 antibacterial peptide selected from rLL-18-1 to rLL-18-2, or a
CC recombinant 30 antibacterial peptide selected from rLL-30-1 to rLL-30-10.
CC Preparing an antibacterial peptide comprises solid-phase chemical method
CC synthesis or genetic engineering expression technology. The antibacterial
CC peptide is useful for preparing a medicament for the treatment of
CC infection caused by Gram-positive bacteria, Gram-negative bacteria, fungi
CC or virus, where the medicament further comprises one or more
CC pharmaceutical carrier or additive. The antibacterial peptide can also
CC reduce side reaction of hemolysis and is easy to prepare. The present
CC sequence is an amino acid sequence of one such rLL-37 antimicrobial
CC peptide of the invention.
XX
SQ Sequence 37 AA;
Query Match 95.7%; Score 178; Length 37;
Best Local Similarity 94.6%;
Matches 35; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 1 LLGDFFRKSKEKIGKGFKRIVQRLKDFLRNLVPRTES 37
||||||||||||||| |||||||:|||||||||||||
Db 1 LLGDFFRKSKEKIGKNFKRIVQRIKDFLRNLVPRTES 37
JP2007169260 teaches an apoptosis inhibitor comprising the amino acid sequence of SEQ ID NO:2, which is 94.6% identical to instant SEQ ID NO:8, for treating different diseases including Parkinson disease (see the sequence alignment below).
SEQ ID NO:8
AGE09075
ID AGE09075 standard; peptide; 37 AA.
XX
AC AGE09075;
XX
DT 06-SEP-2007 (first entry)
XX
DE Partial peptide of human CAP18, SEQ ID 2.
XX
KW bacterial infection; antibacterial; sepsis; immunosuppressive;
KW myocardial infarction; cardiant; vasotropic; cerebral infarction;
KW cerebroprotective; acquired immune deficiency syndrome; anti-hiv;
KW glomerulonephritis; nephrotropic; diabetic nephropathy; antidiabetic;
KW glomerulosclerosis; liver disease; hepatotropic;
KW gastrointestinal disease; gastrointestinal-gen.; viral infection;
KW virucide; immune disorder; immunomodulator; vasoconstriction;
KW dermatological; cerebral ischemia; atrophy; malformation;
KW neurological disease; neuroprotective; lichen; antiinflammatory;
KW antipruritic; transplant rejection; immunosuppressive;
KW motor neurone disease; muscular-gen.; cns-gen.; Alzheimers disease;
KW nootropic; parkinsons disease; antiparkinsonian; nephroblastoma;
KW cytostatic; psychiatric disorder; neuroleptic;
KW cationic antibacterial protein 18; CAP18; apoptosis inhibition;
KW Antimicrobial; therapeutic; pharmaceutical.
XX
OS Homo sapiens.
XX
CC PN JP2007169260-A.
XX
CC PD 05-JUL-2007.
XX
CC PF 10-JUL-2006; 2006JP-00189896.
XX
PR 24-NOV-2005; 2005JP-00339395.
XX
CC PA (JUNT-) GH JUNTENDOU.
CC PA (SEGK ) SEIKAGAKU KOGYO CO LTD.
XX
CC PI Nagaoka I, Hirata M, Tamura H;
XX
DR WPI; 2007-530601/52.
XX
CC PT Apoptosis inhibitor for treating bacterial infection, sepsis, ischemic
CC PT damage, myocardial infarction, nervous function diseases and AIDS,
CC PT comprises antimicrobial peptide, as active ingredient.
XX
CC PS Claim 4; SEQ ID NO 2; 19pp; Japanese.
XX
CC This invention relates to an apoptosis inhibitor which comprises an
CC antimicrobial peptide or a tumor necrosis factor as an active ingredient.
CC The antimicrobial peptide is derived from human and it is preferred that
CC the peptide is chosen from the group which consists of a cationic
CC antibacterial protein (CAP)18, its partial peptide and defensin. CAP18 is
CC an antimicrobial protein discovered from the granulocyte of human or
CC rabbit. The defensin can be a (alpha)-defensin derived from the granules
CC of a neutrophil or (beta)-defensin derived from the epithelial tissues of
CC human. The inhibitor of this invention can be used for suppressing the
CC apoptosis of a neutrophil. The suppression of apoptosis is made through
CC phosphorylation of extracellular signal regulated kinase (ERK), the
CC expression of Bcl-XL, and the active fall of caspase 3. The
CC pharmaceutical composition of this invention is useful for treating
CC bacterial infection, sepsis, myocardial infarction, cerebral infarction,
CC AIDS, glomerulonephritis, diabetic nephropathy, glomerulosclerosis, liver
CC disease, gastrointestinal disease, viral infection, vasoconstriction,
CC cerebral ischemia, immune disorder, atrophy, malformation, neurological
CC disease, lichen, transplant rejection, motor neurone disease, Alzheimers
CC disease, parkinsons disease, nephroblastoma, psychiatric disorder and
CC cancer. The present sequence is a partial peptide of human cationic
CC antibacterial protein (CAP)18.
XX
SQ Sequence 37 AA;
ALIGNMENT:
Query Match 94.6%; Score 176; Length 37;
Best Local Similarity 94.6%;
Matches 35; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 1 LLGDFFRKSKEKIGKGFKRIVQRLKDFLRNLVPRTES 37
||||||||||||||| |||||||:|||||||||||||
Db 1 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES 37
WO2005004794 teaches a cell permeation peptide LL-37 comprising the amino acid sequence of SEQ ID NO:39, which is 94.6% identical to instant SEQ ID NO:8 (see the sequence alignment below).
SEQ ID NO:8
ADW25975
ID ADW25975 standard; peptide; 37 AA.
XX
AC ADW25975;
XX
DT 07-APR-2005 (first entry)
XX
DE LL-37 cell permeation peptide.
XX
KW neuroprotective; nootropic; antiparkinsonian; gene therapy;
KW antisense therapy; expression; pharmaceutical; neurodegenerative disease;
KW antiparkinsonian; neuroprotective; nootropic; LL-37.
XX
OS Unidentified.
XX
CC PN WO2005004794-A2.
XX
CC PD 20-JAN-2005.
XX
CC PF 09-JUN-2004; 2004WO-US018271.
XX
PR 09-JUN-2003; 2003US-0476947P.
XX
CC PA (ALNY-) ALNYLAM PHARM INC.
XX
CC PI Mayo Foundation For Medical Ed, Bumcrot D, Farrer MJ, Maraganore D;
CC PI Vornlocher H;
XX
DR WPI; 2005-091965/10.
XX
CC PT New iRNA agent for treating neurodegenerative disorders comprises an
CC PT antisense strand complementary to a nucleotide sequence of an alpha-
CC PT synuclein RNA, and a sense strand complementary to hybridize to the
CC PT antisense strand.
XX
CC PS Disclosure; SEQ ID NO 39; 190pp; English.
XX
CC The invention describes an iRNA agent comprising an antisense strand
CC complementary to a nucleotide sequence of an alpha-synuclein (SNCA) RNA,
CC and a sense strand complementary to hybridize to the antisense strand.
CC Also described are: treating a human; a pharmaceutical composition
CC comprising the above iRNA agent that targets the alpha-synuclein gene,
CC and a pharmaceutical carrier; reducing the amount of SNCA RNA in a cell
CC of a subject; making an iRNA agent; evaluating an iRNA agent that targets
CC an SNCA nucleic acid; and evaluating an agent for the ability to inhibit
CC SNCA expression. The composition and methods are useful for treating
CC neurodegenerative diseases, such as synucleinopathy, Parkinson's disease,
CC Alzheimer's disease, multiple system atrophy or Lewy body dementia. This
CC is the amino acid sequence of a cell wall permeating peptide suitable for
CC use delivering the siRNA's of the invention into cells.
XX
SQ Sequence 37 AA;
ALIGNMENT:
Query Match 94.6%; Score 176; Length 37;
Best Local Similarity 94.6%;
Matches 35; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 1 LLGDFFRKSKEKIGKGFKRIVQRLKDFLRNLVPRTES 37
||||||||||||||| |||||||:|||||||||||||
Db 1 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES 37
WO2007022506 teaches a cell permeation peptide LL-37 comprising the amino acid sequence of SEQ ID NO:39, which is 94.6% identical to instant SEQ ID NO:8 (see the sequence alignment below).
SEQ ID NO:8
AEX82286
ID AEX82286 standard; peptide; 37 AA.
XX
AC AEX82286;
XX
DT 19-APR-2007 (first entry)
XX
DE Cell permeation peptide SEQ ID NO 39.
XX
KW gene silencing; expression; huntingtin; htt; RNA interference; RNAi;
KW siRNA; short interfering RNA; degeneration; neurological disease;
KW Huntingtons chorea; Parkinsons disease; Alzheimers Disease;
KW multiple system atrophy; dementia; nootropic; anticonvulsant;
KW genetic disorder; cerebroprotective; neuroprotective; antiparkinsonian;
KW gene therapy.
XX
OS Unidentified.
XX
CC PN WO2007022506-A2.
XX
CC PD 22-FEB-2007.
XX
CC PF 18-AUG-2006; 2006WO-US032589.
XX
PR 18-AUG-2005; 2005US-0709985P.
PR 25-JUL-2006; 2006US-0833234P.
XX
CC PA (UYMA-) UNIV MASSACHUSETTS.
XX
CC PI Aronin N, Zamore PD;
XX
DR WPI; 2007-221961/22.
XX
CC PT Downregulating expression of a target gene in a neural cell distal to the
CC PT site of administration by contacting an iRNA agent comprising a sense and
CC PT an antisense strand that form an RNA duplex with the neural cell.
XX
CC PS Disclosure; SEQ ID NO 39; 218pp; English.
XX
CC This invention describes a novel method of downregulating or silencing
CC the expression of huntingtin (htt) by introducing an interfering RNA
CC agent comprising a sense and antisense strand that form an RNA duplex to
CC a neural cell for a time sufficient to allow axonal transport of the iRNA
CC agent into the cell. The interfering RNA agent comprises a lipophilic
CC moiety e.g. cholesterol which is conjugated to the 3'-end of the sense
CC strand. The interfering RNA agent further comprises a phosphorothioate or
CC a 2'-OMe modification. The method is useful in downregulating expression
CC of a target gene in a neural cell distal to the site of administration or
CC in treating a human against a neurological disorder, e.g., Huntington's
CC disease, Parkinson's disease, Alzheimer's Disease, multiple system
CC atrophy, or Lewy body dementia. The antisense strand of the interfering
CC RNA agent comprises a sequence complementary to a sequence comprising a
CC polymorphism of a huntingtin (htt) RNA resulting in an Ala to Cys
CC substitution at position 171. This sequence represents a cell permeation
CC peptide.
XX
SQ Sequence 37 AA;
ALIGNMENT:
Query Match 94.6%; Score 176; Length 37;
Best Local Similarity 94.6%;
Matches 35; Conservative 1; Mismatches 1; Indels 0; Gaps 0;
Qy 1 LLGDFFRKSKEKIGKGFKRIVQRLKDFLRNLVPRTES 37
||||||||||||||| |||||||:|||||||||||||
Db 1 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES 37
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
February 10, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675