DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I (claims 1, 2, 7, 8, 10, 12, 15, 16, 19, 21, 24, 25, 27, and 28, which are directed to a method for increasing Blood CNS Barrier permeability to treat a disease in a subject, comprising administering an inhibitor of the vitronectin-integrin signaling) in the reply filed on 10 Dec, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 30, 31, 33, 35, 36, and 38-40 withdrawn from further consideration pursuant to 37 CFR
l.142(b) as being drawn to a nonelected group of invention.
Accordingly, claims 1, 2, 7, 8, 10, 12, 15, 16, 19, 21, 24, 25, 27, and 28 are examined herein.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application
No. 63/328,122 filed on 06 Apr, 2022
Claim Objections
Claim 25 objected to because of the following informalities: claim 25 recites an abbreviation “RGD” without defining it in the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 7, 8, 10, 12, 15, 16, 19, 21, 24, 25, 27, and 28 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
Claim 1 is drawn to the possession of a method for increasing blood-CNS barrier permeability to treat a disease in a subject comprising administering an inhibitor of the vitronectin-integrin signaling at the blood-CNS barrier. This claim does not require a direct inhibitor of the vitronectin-integrin signaling, rather is interpreted to encompass any inhibitor that directly inhibits vitronectin and/or integrin and any inhibitor that has upstream or downstream effects capable of indirectly promoting inhibition of the vitronectin-integrin signaling pathway. This claim also encompasses treating any disease in a subject.
In regards to a genus of inhibitors:
The specification teaches inhibitors of the vitronectin-integrin signaling comprise of nucleic acids, small molecules, and/or antibodies ([0050]).
nucleic acid inhibitors:
The specification teaches partial structure of nucleic acid inhibitors ([0055]-[0080]), such as having a region of complementarity that is at least 60% to a target region in a mRNA. There is no teaching in the specification regarding which 40% of the structure can be varied while retaining the ability of the nucleic acid to inhibit vitronectin and/or integrin, except that siRNA and shRNA molecules “can be designed and prepared using methods known in the art” ([0058] and [0074]).
Fakhr et al (Cancer Gene Therapy, 2016, 23:73-82) teaches that designing siRNA involves different components, including critical sequence designs matching basic criteria, using different algorithms and online designing software, and finally sufficient efficacy of transferring these siRNAs to the cell for screening and silencing purposes (pg. 80, right-column, third paragraph). Fakhr suggests that “at least three different siRNAs for each gene should be designed to achieve the desired results in gene silencing”, which supports the fact that nucleic acid inhibitors cannot be predicted solely from sequence complementarity, and effective species must be identified through screening and validation.
antibodies:
The specification teaches “the vitronectin inhibitor is an antibody, an antibody variant or an antigen-binding fragment thereof targeting vitronectin…” and additional teachings regarding heavy chain constant domain, VH domain that is “at least 70%...or at least 99% identical to any of the variable chain constant regions provided herein…antibody is modified via glycosylation, phosphorylation, sumoylation, and/or methylation” ([0068]). The specification teaches integrin α5 inhibitor antibodies are known in the art ([0081]). The specification does not disclose the reduction to practice of any species within the claimed genus. There is no teaching regarding which 30% of the structure can be varied while retaining the ability of the antibody to inhibit vitronectin or integrin α5.
Rudikoff et al (PNAS, 1982, 79: 1179-1983) teaches “small number of substitutions in antibodies…be effective in altering antigen-binding specificity” (Abstract). Thus, one of ordinary skilled in the art would not reasonably be able to identify without further testing which of those antibodies having at least 70% identity would still have the ability to inhibit vitronectin or integrin α5.
small molecules and RGD motifs:
The specification teaches actual reduction to practice of one RGD motif bearing one point mutation (Figs 6I, 6J, 6K, 6L; [00136]), and additional RGD ([0083]) and non-peptidic RGD memetic ([0084]) are known in the art. Although the specification did not disclose an actual reduction to practice of small molecule inhibitors, such inhibitors are also known in the art and it can be concluded that Applicant was in possession of this subgenus.
inhibitors that indirectly inhibit the vitronectin-integrin signaling:
It is unknown in the art and not discussed in the disclosure regarding any inhibitor that has upstream or downstream effects capable of indirectly inhibiting the vitronectin-integrin signaling. No structure, chemical properties, functional characteristics, or working examples are provided.
In summary, although the disclosure and state of the art provides sufficient written description for possession of small molecules and RGD motif inhibitors, Applicant was NOT in possession of this genus of inhibitors of the vitronectin-integrin signaling.
In regards to a genus of a disease:
The specification does NOT disclose reduction to practice a method for increasing Blood-CNS barrier permeability to treating any disease, and the state of the art does NOT disclose any disease treatable with the claimed method. Thus, Applicant was NOT in possession of this claimed genus.
Dependent claims 10, and 19 recite another subgenus of inhibitory nucleic acids targeting VTN and ITGA5, and the specification teaches the following:
siRNA molecules can be different length, from 7 to 100 or more nucleotides ([0059]-[0066]), and comprises a nucleotide sequence that is “at least 60%...or 100% identical to the sequences set forth in SEQ ID NOs: 7 or 8 ([0063]) and 9 or 10 ([0064]).
shRNA molecules targeting ITGA5 can be of different length from 7 to 50 or more nucleotides ([0071]-[0075]), “the region of complementarity is at least 60%...or 100% complementary to a target region in a ITGA5 mRNA” ([0076]), “the region of complementarity is 5…or 50 nucleotides in length” ([0077]), and “comprises nucleotide sequences that is at least 60%...or 100% identical to the sequences as set forth in SEQ ID NOs: 3 or 4” ([0078]-[0080]).
There is no teaching in the specification regarding which 40% of the structure can be varied while retaining the ability of the nucleic acid to inhibit vitronectin and/or integrin, except that siRNA and shRNA molecules “can be designed and prepared using methods known in the art” ([0058] and [0074]).
Taxman et al (RNA Therapeutics. Methods in Molecular Biology, 2010, 629: 139-156) teaches “a minimum of two target sequences (i.e., shRNA) should be designed for each gene, in order to increase the likelihood that at least one sequence results in significant gene knockdown” (pg. 141, second paragraph). Taxman further teaches that “RNAi sequences have been constructed from 19 to 27 bp, most data on effective sequence selection involve the design of 19 bp targets” (pg. 141, second paragraph). The state of the art does not support siRNA and shRNA sequences having the required inhibition activity can range from 5 or 7 to 100 or more nucleotides as stated in the specification.
Thus, based on the lack of knowledge and unpredictability in the art, it is concluded that Applicant was not in possession of the claimed subgenus of inhibitory nucleic acids in claims 10 and 19 based on disclosure of the single species of SEQ ID NOs: 3, 4, 7-10.
Dependent claims 12 and 21 recite four specific siRNA and shRNA inhibitors, SEQ ID NO 7, 8, 3, and 4, targeting VTN and ITGA5, and the specification teaches an actual reduction to practice of these species to increase blood-CNS barrier permeability (for siRNA: Fig 11A-C, [00129] and for shRNA: Figs. 7E and 7F; [00138]). Thus, the specification provides adequate written description for claims 12 and 21.
Dependent claims 15 and 24 recite a subgenus of antibody inhibitors, and as discussed above in claim 1, Applicant was not in possession of this claimed subgenus.
Dependent claim 25 recites a subgenus of peptide containing RGD or non-peptidic RGD mimic, and as discussed above in claim 1, Applicant was in possession of this claimed subgenus.
Dependent claims 27 and 28 recited a subgenus of therapeutic agent and neuromuscular disease. The specification teaches “the identity of such CNS therapeutic agents are known in the art and described, e.g., Pardridge et al (NeuroRx, 2005, 2: 3-14)” ([0092]), neuromuscular disease is selected from group consisting of Amyotrophic Lateral Sclerosis, Ataxia, Cerebral Palsy, Muscular Dystrophy)” ([0092]). The specification discloses the reduction to practice of HRP Fig 11A-C, [00129]) and a FM1-43FX dye (Figs. 7E and 7F; [00138]) with siRNA and shRNA inhibitors, and did not disclose reduction to practice treating any disease.
Pardridge teaches that “98% of all small molecules do not cross the blood-brain barrier (BBB) (i.e., blood-CNS barrier) and all large-molecule products such as monoclonal antibodies, recombinant proteins, antisense, or gene therapeutics do not cross the BBB (FIG. 1, pg. 3, left-column, second paragraph). Pardridge further teaches “these drugs generally only treat certain CNS disorders, such as epilepsy, affective disorders, and chronic pain” (pg. 12, right-column, first paragraph). Therefore, HRP and FM1-43FX dye are NOT representative species based on their size and solubility compared to effective therapeutic agents for CNS disorders. Based on the lack of knowledge on treating neuromuscular diseases and unpredictability of therapeutic agents being able to cross the BBB, it is concluded that Applicant was not in possession of the claimed subgenus of in claims 27 and 28.
Based on the preponderance of the evidence, including relevant teachings of the specification, the absence of working examples, and the state of prior art including knowledge of inhibitors of the vitronectin-integrin signaling and methods for increasing blood-CNS barrier permeability to treat a disease in a subject, Applicant was not in possession of the claimed method.
Claim Rejections - 35 USC § 112 – Enablement
Claims 1, 2, 7, 8, 10, 12, 15, 16, 19, 21, 24, 25, 27, and 28 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not reasonably provide enablement for the use of a method for increasing Blood-CNS barrier permeability to treat a disease in a subject, comprising administering an inhibitor of the vitronectin-integrin signaling at the Blood-CNS barrier. 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 the claims.
The test of enablement is whether one skilled in the art could make and use the claimed
invention from the disclosures in the specification coupled with information known in the art without
undue experimentation {United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue
experimentation is needed is not based upon a single factor but rather is a conclusion reached by
weighing many factors. These factors were outlined in Ex pa rte Forman, 230 USPQ 546 (Bd. Pat. App. &
Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are
indicated below:
Nature of the Invention and Breadth of Claims
With respect to claim breadth, the standard under 35 U.S.C. §112(a) entails determining what
the claims recite and what claims mean as a whole. The nature of the invention is directed to a method for increasing Blood-CNS barrier permeability to treat a disease in a subject, comprising administering an inhibitor of the vitronectin-integrin signaling. Under the broadest reasonable interpretation (BRI), the claimed invention encompasses a method in which increasing Blood-CNS permeability is itself a treatment of a disease. The claim merely recites administering to the subject “an inhibitor of the vitronectin-integrin signaling at the Blood-CNS Barrier”, which under BRI, is interpreted as any administration of any inhibitor that directly and indirectly inhibits the vitronectin-integrin signaling at the Blood-CNS Barrier. Claim 27 recites administering a therapeutic agent, and claim 28 recites wherein the disease is a neuromuscular disease. Thus, the claims broadly recite a method for increasing Blood-CNS Barrier permeability to treat any neuromuscular disease comprising administering any therapeutic agent and any inhibitor capable of inhibiting the vitronectin-integrin signaling at the Blood-CNS Barrier.
Guidance of the Specification and State of the Art
a) treating a disease in a subject
The specification does NOT disclose any working example in which any disease was treated by increasing blood-CNS barrier permeability or inhibiting the vitronectin-integrin signaling. Instead, the specification discloses that treatment of a disease in a subject is “in combination with a therapeutic agent to the CNS” ([0092]). Further, the state of the art also does NOT disclose any disease associated with the vitronectin-integrin signaling or any disease that can be treated by merely increasing blood-CNS barrier permeability or inhibiting the vitronectin-integrin signaling.
b) therapeutic agent
The specification teaches “CNS therapeutic agents are known in the art” ([0092]). However, the specification does NOT disclose any working examples with any therapeutic agent to treat a disease in a subject because the vitronectin or integrin-knockout mice in experimental data did not have “a disease affecting the CNS” in accordance with the definition regarding “a subject” provided by the specification ([0090]), and no therapeutic agent was introduced.
Pardridge et al (NeuroRx, 2005, 2: 3-14) cited by Applicant in the specification ([0092]), teaches that “98% of all small molecules do not cross the blood-brain barrier (BBB) (i.e., blood-CNS barrier) and all large-molecule products such as monoclonal antibodies, recombinant proteins, antisense, or gene therapeutics do not cross the BBB (FIG. 1, pg. 3, left-column, second paragraph). Pardridge further teaches “small molecules generally cross the BBB in pharmacologically significant amounts if 1) the molecular mass of the drugs is less than 400-500 Da, and 2) the drug forms less than 8-10 hydrogen bonds with solvent water” (pg. 5, left-column, second paragraph), and “these drugs generally only treat certain CNS disorders, such as epilepsy, affective disorders, and chronic pain” (pg. 12, right-column, first paragraph). Therefore, Pardridge’s teachings positively demonstrate the limited number of available therapeutic agents for CNS disorders and the significant challenges in delivering these therapeutic agents across the BBB due to their size and solubility. Further, Pardridge’s teachings support the conclusion that the specification lacks evidence of the claimed method with merely experimental data demonstrating an increase of HRP-filled vesicles of 40 kDa (Figs 6I, 6J, 6K, 6L; [00136]) and a FM1-43FX dye of 560 Da (Figs. 7E and 7F; [00138]) across the BBB without determining whether pharmacologically significant amounts of actual therapeutic agents can cross the BBB to be able to treat a disease in a subject upon inhibiting the vitronectin-integrin signaling. Considering the teachings of Pardridge, it can also be concluded that extrapolating from one large-molecule and one molecule slightly larger than the 500 Da threshold of small molecules that generally cross the BBB to effective and safe treatment of a disease in a subject is not routine or predictable.
c) inhibitors of the vitronectin-integrin signaling
The specification teaches inhibitors comprise of nucleic acids ([0055]-[0080]), antibodies ([0081]), RGD ([0083]), and non-peptide RGD memetics ([0084]). The specification also teaches the following working examples where increased blood-CNS barrier permeability was observed:
siRNA vitronectin-knockout mice where horseradish peroxidase (HRP)-filled vesicles were transcytosed across retinal and cerebellum endothelial cells (Fig 11A-C, [00129]).
mice bearing a single point mutation RGE motif exhibited a >2-fold increase in HRP-filled vesicles in endothelial cells (Figs 6I, 6J, 6K, 6L; [00136]), as compared to mice bearing a wild-type RGD motif where vitronectin binds with integrin receptors
shRNA integrin-knockout cells exhibited endocytosis of a FM1-43FX dye (Figs. 7E and 7F; [00138])
mice containing acute deletion of endothelial Itga5 (Figs 8G and 8H; [00140]), in contrast to Itgav that is predominantly in pericytes (Figs 15B-15D).
The specification does not provide the following evidence:
any inhibitor that increases the permeability of the blood-CNS barrier in the subject by at least 10%...at least 500% or more” ([0089])
any nucleic acid inhibitors other than one siRNA and one shRNA
any inhibitor that can increase the permeability of the blood-CNS barrier such that, e.g., a therapeutically effective dose of the CNS therapeutic agent is able to reach the CNS or the necessary dose of the CNS therapeutic agent is lowered” ([0094]). An increased in transcytosis of HRP-filled vesicles (Figs 6I, 6J, 6K, 6L; [00136]) or endocytosis of a FM1-43FX dye (Figs. 7E and 7F; [00138]), do not support the claimed invention because they are not therapeutic agents for any disease and their increased uptake is not evidence that “a therapeutically effective dose of the CNS therapeutic agent is able to reach the CNS or the necessary dose of the CNS therapeutic agent is lowered”.
Slack et al (Nat Rev Drug Discov, 2022, 21: 60-78) teaches inhibitors of integrin and integrin-targeted therapies are established in the art, and such inhibitors include antibodies, peptide, and small molecules (Fig. 1). Slack further teaches these inhibitors are used to treat diseases such as fibrosis, cancer, cardiovascular disease, macular degeneration, and etc (Fig. 1). However, prior art does NOT disclose or suggest that integrin inhibitors increase blood-CNS permeability, nor that such an effect can treat a disease.
d) inhibitors of integrin α5 recited in claims 7 and 16
The specification and prior art teach such integrin α5 inhibitors are characterized and known in the art. For instance, Hu et al (Experimental Eye Research, 2019, 180: 43-52) teaches a small molecule THR-687 is a RGD antagonist for integrin α5β1 among other integrins and has therapeutic effect in the context of diabetic retinopathy and wet age-related macular degeneration (Abstract, and Table 1), not neuromuscular diseases. Stregies et al (J. Med. Chem., 2007, 50: 3786-3794; Cited on IDS received on 10 December 2025) teaches non-peptide RGD memetic as integrin α5β1 antagonists (Abstract). Kapp et al (Scientific Reports, 2017, 7:39805; Cited on IDS received on 15 August 2023) teaches a series of integrin α5β1 antagonists containing RGD exhibiting sufficient activity and selectivity to effectively discriminate between two closely related integrin subtypes, α5β1 and αvβ3 (Table 1). Other known α5β1 antibodies and non-peptidic RGD memetics are also described in the specification ([0081], [0083], and [0084]).
Despite integrin α5 inhibitors are known in the art, the claimed method requires integrin α5 to interact with vitronectin as claim 1 recites “inhibition of the vitronectin-integrin signaling”, and state of the art at the effective filling date does not teach or suggest that vitronectin interacts with integrin α5. Jia et al (Experimental Neurology, 2019, 312: 20-32) teaches that vitronectin are released by pericytes to regulate the BBB permeability (pg. 29, left-column, first paragraph), and vitronectin “is known to promote endothelial cell survival, probably through αvβ3 integrin…and is an adhesion molecule for astrocytes, binding to αvβ5 integrin (pg. 29, left-column, second paragraph). Although Ayloo et al (Neuron, 2022, 110:1641-1655; Cited on IDS received on 15 August 2023) published after the effective filling date teaches that vitronectin interacts with integrin α5, this art CANNOT be relied upon to supply missing teachings for enablement of the present claims.
Thus, while integrin α5 inhibitors are generally known, the state of the art does not teach interaction of vitronectin and integrin α5 recited in instant claims 7 and 16, nor such inhibitors can increase blood-CNS barrier permeability.
In summary, as of the filling date, there is no prior art disclosing increasing Blood-CNS Barrier permeability to treat any disease in a subject by inhibiting the vitronectin-integrin signaling. The state of the art does not provide guidance on any inhibitors of the vitronectin-integrin signaling capable of increasing Blood-CNS barrier permeability and any method to treat a disease in a subject by increasing Blood-CNS barrier permeability without substantial and unpredictable experimentation.
Experimentation Required
For example, it would be necessary for one of ordinary skill in the art to conduct the following experimentation in order to practice the claimed invention:
screening inhibitors of i) vitronectin, ii) integrin a5, and iii) vitronectin-integrin signaling pathway capable of increasing Blood-CNS Barrier permeability by “at least 10% or more” ([0089])
screening therapeutic agents of different sizes for a specific neuromuscular disease which upon an increase of blood-CNS barrier permeability, a therapeutic effective dose of therapeutic agents is able to reach the CNS or the necessary dose of the therapeutic agent is lowered
determining any changes in in vivo dosing, pharmacokinetics, formulations and drug stability for therapeutic agents
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the Applicant and the specific examples, it is concluded that an unreasonable amount of experimentation would be required to make and use the invention as claimed.
Conclusion
No claims are allowable.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/ Supervisory Patent Examiner, Art Unit 1636