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 .
Applicant's arguments and amendments to the claims filed on 09-18-2025 have been received and entered. Claim 50-65, 69-73, 75-76 has been amended. Claims 1-49, 66-68, 74, 78 have been canceled. Claim 79 have been added. Claims 50-65, 69-73, 75-77, 79 are pending.
This is a Non-Final action on the merits.
Election/Restrictions
Applicant's election with traverse of ischemic condition, ischemia of the limb and an activator of Notch 4 in the reply filed on 02-09-2024 is acknowledged. The traversal is on the ground(s) that all claims read on the elected species and examination of all species would not be a burden to the Examiner. This is not found persuasive because this application is a 371 of PCT/US2019/043538 07/25/2019, and This application contains claims directed to more than one species of the generic invention. These species are deemed to lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1. The species were listed in the preceding Office Action mailed on 12-13-2023. The claims and species encompass different diseases/disease conditions (such as Ischemic condition, artery disease, atherosclerosis or diabetes etc.), different organs (such as eye, spleen, brain etc.), different drugs/compounds/ peptides/proteins (such as Notch intracellular domain, N-methylhemeanthidine chloride, valproic acid, resveratrol, antibody etc.). Different diseases and conditions differ physiologically and pathologically and they have to be considered individually. Different drugs/ compounds/ peptides or proteins differ in their chemical structures and biological functions, and they have to be considered individually. There would be serious burden for Examiner to search and examine all groups. The requirement is still deemed proper and is therefore made FINAL.
However, upon further consideration, all the species of Notch activating agent are rejoined.
Claims 53-56, 58-59 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 02-09-2024.
Claims 50-52, 57, 60-65, 69-73, 75-77 and 79, which read on species of ischemic condition, ischemia of the limb and are under consideration.
Priority
This application is a 371 of PCT/US2019/043538 filed on 07/25/2019 that claim priority from US provisional application 62/703,872 filed on 07/26/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09-18-2025 is in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Specification
The clean and marked-up copies of the substitute specification with the paragraph renumbering were received on 9/18/2025 is acknowledged. All references to paragraph numbers in the action will be as per the amended specification.
New-Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 50-52, 57, 60-65, 69-73, 75-77 and 79 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.
Base claim 50 is directed to a method of increasing blood flow in a tissue of a subject, wherein the tissue is afflicted with a condition wherein blood flow is reduced, impeded, or blocked in one or more blood vessels of the tissue; comprising administering a pharmaceutically effective amount of a Notch-activating agent into an artery specifically to arterial cells in the tissue, wherein the Notch-activating agent binds to a Notch receptor on the arterial cells; or the Notch-activating agent is a Notch receptor intracellular domain that is directly administered into arterial cells in the tissue.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. 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. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304,312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43). USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
The claims encompass a genus of method of increasing any type of blood flow in any type of tissue of a subject, wherein the tissue is afflicted with a condition wherein any type of blood flow is reduced, impeded, or blocked in one or more blood vessels of the tissue; comprising administering a pharmaceutically effective amount of any type of Notch-activating agent into an artery specifically to arterial cells in the tissue, wherein the Notch-activating agent binds to a Notch receptor on the arterial cells; or the Notch-activating agent is a Notch receptor intracellular domain that is directly administered into arterial cells in the tissue.
The specification teaches Example 1. Mice with Inducible Arterial Notch Signaling: To study the effects of Notch signaling in mouse models of ischemia, constitutively active forms of Notch1 and Notch4 were used, denoted Notch1 ICD and Notch4*, respectively. Notch1 ICD comprises a truncated Notch1 receptor intracellular domain (ICD) without the transmembrane or extracellular domains, functionally replicating a cleaved Notch intracellular domain and being constitutively active upon expression ([0098] of the Marked-Up Specification); Example 2. Artery activation of Notch signaling through Notch1 intracellular domain (ICD) expression promotes recovery in a mouse model of ischemic stroke: Neurological function was tested pre- and post-dMCAO. Arterial activation of Notch1 improved neurological recovery after dMCAO. Neurological functions were assessed (Fig. 1A), and quantification of infarct volume showed significantly less (p<0.01) infarct volume in BMX-Notch1 ICD mice, compared with control mice. (Fig. 1B) ([0103] of the Marked-Up Specification). Neurological functions were assessed (Fig. 2A), including by modified bederson's grading, elevated body swing test, ladder test, and adhesive test. Quantification of infarct volume showed significantly less (p<0.01) infarct volume in BMX-Notch4* mice, compared with control mice (Fig. 2B) ([0105] of the Marked-Up Specification); Example 3. Post-ischemic Notch signaling activation promotes neurological recovery, reduction of infarct volume, and increased growth of collateral arteries ([0108] of the Marked-Up Specification): Prior to and following dMCAO ischemic injury, neurological functions were assessed (Fig. 3A), including by modified bederson's grading, elevated body swing test, ladder test, and adhesive test. Quantification of infarct volume determined by H&E staining showed significantly less infarct volume in BMX-Notch1 ICD mice, compared with control mice (Fig. 3B) ([0109] of the Marked-Up Specification); Example 4. Durable effects of transient Notch signaling induction on post-ischemic recovery: To further investigate the effects of upregulated Notch signaling following ischemic injury in the brain, an experiment was performed as summarized in Fig. 5A ([0112] of the Marked-Up Specification). Collateral artery diameter, velocity, and flux (Fig. 5B) were all improved in BMX-Notch1 ICD mice, compared to control mice ([0114] of the Marked-Up Specification); Example 5. Therapeutic Effects of Notch Signaling Activation by Administration of a Notch Ligand: The foregoing experiments demonstrated the therapeutic effects of Notch signaling in ischemic brain injury by genetic approaches. To further demonstrate the therapeutic effects of upregulated Notch signaling following ischemic brain injury, recombinant mouse DLL4 was administered to wild type mice (C57BL/6Jstrain) daily, starting from the day before dMCAO for eight days, by intravenous injection at a dosage of 1 microgram per gram body weight for the first three doses and 0.8 micrograms per day thereafter, as summarized in Fig. 6A. Collateral artery size and function was assessed at seven and fourteen days following injury. In mice treated with rDLL4, collateral artery diameter, velocity, and flux (Fig. 6B) was significantly improved at day 7, at which time rDLL4 administration was halted. Significant improvements in the treated mice persisted at day 14. Neurological function, as assessed by the ladder test at day 15 and 17, was higher in the treated mice (Fig. 6C) ([0116] of the Marked-Up Specification); Example 6. Upregulation of Notch Signaling Improves Recovery in Acute Limb lschemia Model: Fig. 7A depicts improved blood flow in the ischemic foot of Notch4* expressing mice. Fig. 7B depicts improved recovery in hindlimb artery diameter in BMX-Notch4* mice, while no off-target effect was seen in the unoperated limb. Fig. 7C depicts the ratio in the change of collateral artery diameter after EFAO between operated and unoperated limbs. Fig. 8 depicts significantly reduced muscle necrosis in BMX-Notch4* mice at day-7 after EFAO. Compared to control mice, foot blood flow was greater in the ischemic limbs of the BMX-Notch4* mice, becoming significantly improved by day 7 and remaining so for the remainder of the 56-day time course of measurement (Fig. 9). ([0118] of the Marked-Up Specification).
1. The claims lack written description because, depending on the context, not all activated Notch receptors in an arterial cell can lead to increased blood flow for the tissue comprising the arterial cell:
Baron-Menguy et al (Hypertension, 2017;69:60-70. DOI: 10.1161/HYPERTENSIONAHA. 116.08015) teach increased Notch3 activity mediates pathological changes in structure of cerebral arteries (title): Baron-Menguy et al investigated “the contribution of TIMP3 and Notch3 signaling to the impairment of maximal vasodilator capacity caused by the archetypal R169C mutation. Maximally dilated cerebral arteries in TgNotch3R169C mice exhibited a decrease in lumen diameter over a range of physiological pressures that occurred before myogenic tone deficits ……. Reduced maximal vasodilation was prevented by conditional reduction of Notch activity in smooth muscle of TgNotch3R169C mice and mimicked by conditional activation of Notch3 in smooth muscle, an effect that was blood pressure–independent. We conclude that increased Notch3 activity mediates reduction in maximal dilator capacity of cerebral arteries in CADASIL and may contribute to reductions in cerebral blood flow” (Abstract). Baron-Menguy et al teach that the Notch3 receptor is predominantly expressed in arterial SMCs and is a critical regulator of the developmental formation of small arteries, especially in the brain. Importantly, both in vivo and in vitro studies have documented a role for Notch3 in the rearrangement of the SMC cytoskeleton.20 Motivated by these results, we here examined the possible role of TIMP3 and Notch3 signaling in mutant Notch3-mediated reductions in lumen diameter (Page 61, left column, 2nd para.). Baron-Menguy et al teach CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy) is a paradigmatic Cerebral small vessel diseases (cSVDs) that commonly occurs in normotensive individuals. TgNotch3R169C mice, a well-established model of CADASIL, develop reduction in lumen diameter of cerebral arteries in the absence of chronic hypertension, and the magnitude of the reduction is in the same range as that seen with chronic hypertension. This change, which reduces vasodilator capacity, may adversely affect local cerebral blood flow and thereby contributes to the disease phenotype; yet, the underlying molecular mechanisms have remained unknown. The current study highlights an association between an unsuspected increase in Notch3 activity and the R169C archetypal CADASIL mutation and uncovers a previously unknown role of increased Notch3 activity in structural changes that lead to smaller lumen diameter, that is, blood pressure–independent. We speculate that increased Notch3 activity and reduced vasodilator capacity are common features of many other CADASIL mutations. Further in-depth studies are needed to understand how increased Notch3 activity affects structure of cerebral arteries (Page 68, right column, bridging last paragraph to page 69).
Segarra et al (Blood First Edition paper, June 24, 2008; DOI 10.1182/blood-2007-11-126045.) teach Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth (title): Gene targeting experiments have shown that Delta-like 4 (Dll4) is a vascular specific Notch ligand critical to normal vascular development. Recent studies have demonstrated that inhibition of Dll4/ Notch signaling in tumor-bearing mice resulted in excessive, yet nonproductive tumor neovascularization and unexpectedly reduced tumor growth …… These results demonstrate that Notch activation in the tumor microenvironment reduces tumor neovascularization and blood perfusion, and suggest that Dll4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors (Abstract).
Potts et al (Arterioscler Thromb Vasc Biol. 2025;45:845–856. DOI: 10.1161/ATVBAHA.124. 321690) teach NOTCH signaling networks in perivascular adipose tissue (title): Due to the strong activity of NOTCH in regulation of metabolic function, activation of the NOTCH network in specific cell types in perivascular adipose tissue has implications for signaling to the underlying blood vessel and control of vascular health and disease (Abstract). Potts et al teach the impact of activated NOTCH signaling in PVAT (perivascular adipose tissue) was seen in vasoreactivity of the underlying vessel, where the aorta contracted more to stimuli and had impaired dilation (Page 852, right column, last para.). Potts et al teach current Notch research in mouse models shows several limitations in translating findings to human health. First, the current mouse model used to study Notch-associated diseases, such as cardiovascular diseases, cannot totally replicate the human condition due to the complexity of human pathologies. Second, noncanonical Notch signaling, which also plays roles in cardiovascular function, has been mostly studied in mice. There is a knowledge gap in defining the roles of noncanonical Notch in human physiology and pathologies. Last, the function of Notch signaling is cell context dependent, which makes it challenging to summarize findings from different model organism studies to benefit human health. Future studies should also focus on developing a humanized cardiovascular disease model that can improve the external validity of the findings in animal studies. In addition, context-specific studies need to be conducted to dissect the roles of different components of Notch signaling, including those in the noncanonical Notch pathway (e.g., transmembrane domain), in regulating human physiology (Page 854, left column, 1st para.).
2. Further, the claims lack written description that encompass for a genus of Notch-activating agent. According to the specification of the claimed invention, the Notch-activating agent comprises any composition of matter which increases Notch signaling in cells of the body, for example, blood vessel endothelial cells, for example arterial endothelial cells. The Notch activating agent may comprise any agent having Notch activating activity, including, for example, antibodies, small molecules, peptides and proteins, and nucleic acids ([0056], Marked Up Specification). However, these Notch activating agents encompass several species that are unpredictable functionally and structurally with regards to blood flow: Benedito et al (Cell 137, 1124–1135, June 12, 2009, DOI 10.1016/j.cell.2009.03.025) teach Dll4 (Delta-like 4) and Jagged1 (Jag1) which are ligands that activate Notch signaling, including Notch 1: The Notch Ligands Dll4 and Jagged1 have opposing effects on angiogenesis (title). Benedito et al stated that “the Notch pathway is a highly conserved signaling system that controls a diversity of growth, differentiation, and patterning processes. In growing blood vessels, sprouting of endothelial tip cells is inhibited by Notch signaling, which is activated by binding of the Notch receptor to its ligand Delta-like 4 (Dll4). Here, we show that the Notch ligand Jagged1 is a potent proangiogenic regulator in mice that antagonizes Dll4-Notch signaling in cells expressing Fringe family glycosyltransferases. Upon glycosylation of Notch, Dll4-Notch signaling is enhanced, whereas Jagged1 has weak signaling capacity and competes with Dll4. Our findings establish that the equilibrium between two Notch ligands with distinct spatial expression patterns and opposing functional roles regulates angiogenesis, a mechanism that might also apply to other Notch-controlled biological processes” (Abstract).
Pedrosa et al (Arterioscler Thromb Vasc Biol. 2015;35:1134-1146. DOI: 10.1161/ATVBAHA.114.304741.) teach endothelial Jagged1 antagonizes Dll4 regulation of endothelial branching and promotes vascular maturation downstream of Dll4/Notch1 (title): Pedrosa et al teach “Notch signaling controls cardiovascular development and has been associated with several pathological conditions. Among its ligands, Jagged1 and Dll4 were shown to have opposing effects in developmental angiogenesis, but the underlying mechanism and the role of Jagged1/Notch signaling in adult angiogenesis remain incompletely understood ….. Endothelial Jagged1 is likely to operate downstream of Dll4/Notch1 signaling to activate Notch4 and regulate vascular maturation. Thus, Jagged1 not only counteracts Dll4/Notch in the endothelium but also generates a balance between angiogenic growth and maturation processes in vivo (Abstract).
Thus, both Dll4 (Delta-like 4) and Jagged1 (Jag1) are ligands that activate Notch signaling, including Notch1, but they have opposing roles, especially in blood vessel formation (angiogenesis), where Dll4 is a strong inhibitor of sprouting (tip cell formation for angiogenesis) while Jagged1 can antagonize Dll4 signaling to promote vascular growth and maturation, depending on the context and cell type. Dll4: Generally considered a stronger activator of Notch1 in endothelial cells, promoting stalk cell differentiation and inhibiting tip cell formation, thus restricting excessive sprouting. Jagged1: Can activate Notch receptors (including Notch1 and Notch2), but in the context of blood vessels, it often acts as an antagonist to Dll4, promoting vascular stability and maturation by reducing Dll4's inhibitory signal. Therefore, as an example, notch1 signaling is context dependent. The same receptor produces very different vascular outcomes depending on which ligand engages and under which conditions, and activating the same Notch receptor using Notch-activating agent is unpredictable in the context of increasing blood flow.
There is no evidence on the record that the Notch-activating agents defined in the instant disclosure “Notch-activating agent comprises any composition of matter which increases Notch signaling in cells of the body ……. for example, antibodies, small molecules, peptides and proteins, and nucleic acids ([0056], Marked Up Specification)” had known structural relationships to each other; the art references indicated that there are structural and functional differences between Notch-activating agents. The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 UsPQ2d 1641, 1646 (1998).
The specification lacks sufficient variety of species to reflect this variance in the genus showing (i) any Notch receptor activation on arterial cells would result in increasing blood flow in any context any tissue any physiological/pathological condition and (ii) contemplated biological activity of Notch-activation of any composition of matter such as antibodies, small molecules, peptides and proteins, and nucleic acids. The specification does not provide sufficient descriptive support for the myriad of variant embraced by the claims.
Overall, what these statements indicate is that the Applicant must provide adequate description of such core structure and function related to that core structure such that the Artisan of skill could determine the desired effect. Hence, the analysis above demonstrates that Applicant has not determined the core structure for full scope of the claimed genus for contemplated any Notch receptor activation on arterial cells by any composition of matter would result in increasing blood flow in any context
The skilled artisan cannot envision the detailed functions/structures of any composition of matter working as Notch activating agents that activate any Notch receptor on arterial cells and result in increasing blood flow in any context other than those described in the specification, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. 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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v.Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
New-Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 76 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 76 depend from claim 74 which has been canceled. It is unclear the metes and bounds of the claims. Appropriate correction is required.
For the sake of compact prosecution, claim 76 is interpreted as being depending from claim 75.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 50-52, 57, 61-65, 69-73, and 79 were rejected under 35 U.S.C. 103 as being unpatentable over Simons et al (Pub. No.: US 2014/0120106 Al, Pub. Date: May 1, 2014) in view of Trindade et al (Blood, 1 September 2008, Volume 112, Number 5, DOI 10.1182/blood-2007-09-112748.) as evidenced by Shutter et al (Genes & Development 14:1313–1318, 2000, doi:10.1101/gad.14.11.1313). In view of Applicants' amendment of base claim 50, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
New-Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(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 50, 51, 52, 64-65, 69, 70, 77, 79 are rejected under 35 U.S.C. 102 (a2) as being anticipated by Arboleda–Velasquez (US 2020/0102384 A1, Provisional application No.62/477,289, filed on Mar. 27, 2017.).
Claim interpretation:
The specification of the claimed invention teaches that “the scope of the invention encompasses the administration of a Notch-activating agent. The Notch-activating agent comprises any composition of matter which increases Notch signaling in cells of the body, for example, antibodies, small molecules, peptides and proteins, and nucleic acids” ([0056] of the Marked-Up Specification), and “the Notch-activating agent is a nucleic acid, for example a genetic construct which is delivered to target cells and expressed by such cells ……… The construct codes for a Notch ligand, for example, DLL1, DLL2, DLL3, DLL4, Jagged 1, Jagged 2, or variants of a Notch ligand” ([0064] of the Marked-Up Specification). Thus, any composition of matter such as antibodies is interpreted as a Notch-activating agent.
The specification of the claimed invention teaches that “given that the target cells are blood vessel cells, the administration of the Notch-activating agent will be by intravenous route” ([0192] of the Marked-Up Specification) and “DLL4 was administered to wild type mice (C57BL/6Jstrain) daily, starting from the day before dMCAO for eight days, by intravenous injection” (Example 5, [0116] of the Marked-Up Specification). Thus, “directly administered into arterial cells” is interpreted as encompassing systemically intravenous injection of Notch-activating agent.
Regarding to claims 50, 69-70, 77, 79, Arboleda–Velasquez teaches that aspects of the present subject matter relate to the use of NOTCH3 agonists for the treatment of a wide variety of Cerebral small vessel diseases (SVD), including but not limited to cerebral small vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), age-related macular degeneration (AMD), cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) ([0007], page 1). Aspects provide methods of administering a NOTCH3 agonist to a person who has or is at risk of suffering from a SVD, and in various embodiments, the subject has arterial hypertension ([0009], page 1) (For claim 50).
Arboleda–Velasquez teaches “provided are methods of treating SVD, including CADASIL and NOTCH3 loss of function-associated SVD, with a Notch agonist. Exemplary agonists include antibodies, e.g., monoclonal antibodies that bind to the ectodomain (SEQ ID NO: 12) of NOTCH3. Such antibodies activate the receptor” ([0033], page 4). Arboleda–Velasquez teaches “"Administering" an agonist described herein can be effected or performed using any of the various methods and delivery systems known to those skilled in the art. The administering can be, for example, intravenous, oral, ocular (e.g., subconjunctival, intravitreal, retrobulbar, or intracameral), intramuscular, intravascular, intra-arterial, intracoronary, intramyocardial, intraperitoneal, subcutaneous, inhaled, or intrathecal. Other non-limiting examples include topical administration, or coating of a device to be placed within the subject. In embodiments, administration is effected by injection or via a catheter.” ([0213], page 34) (For claims 50, 69-70, 77, 79).
Further, Arboleda–Velasquez teaches “Non-limiting examples of NOTCH3 agonists include any molecule, e.g., an antibody, that can produce an activated signaling form of the receptor, including soluble ligands of the receptor, antibodies and fragments thereof, small molecules that bind NOTCH3 extracellularly or that can enter the cell and act intracellularly, molecules that have enzymatic activity in cleaving the receptor to release the activated form, and molecules with the ability to destabilize the negative regulatory region of the receptor” ([0166], page 27) (For claim 50).
Regarding to claim 51, Arboleda–Velasquez teaches “NOTCH3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue, and SYD may be treated by modulating NOTCH3 signaling” ([0033], page 4). Arboleda–Velasquez teaches Example 1: therapeutic targeting of NOTCH3 signaling prevents mural cell loss in small vessel disease: “This Example discloses the characterization of a mouse model of SVD in which mural cell coverage in arteries depends upon human NOTCH3 function, a cell signaling mechanism associated with SYD and mural cell pathology in humans. The data presented herein shows that arteriolar degeneration linked to Notch mutations is suppressed by Notch signaling activation. Without being bound by any scientific theory, the data herein show Notch loss of-function (and not Notch toxic gain-of-function or neomorphism) as the relevant mechanism in SVD” ([0370], page 43). Thus, Arboleda–Velasquez teaches increasing blood flow by reducing the resistance of blood vessels.
Regarding to claim 52, Arboleda–Velasquez teaches NOTCH3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia ([0117], page 24). The present subject matter provides methods for the treatment of each subtype, symptom, and/or complication of myocardial ischemia ([0119], page 24)
Regarding to claims 64-65, Arboleda–Velasquez teaches “the NOTCH3 agonist will bind NOTCH3 receptor, and as well, initiate or mediate the signaling event associated with the NOTCH3 receptor, such as, for example, to cause the intracellular domain of NOTCH3 to be released for nuclear translocation.” ([0166], page 27).
Thus claims 50, 51, 52, 64-65, 69, 70, 77, 79 are being anticipated by Arboleda–Velasquez.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 60-63 are rejected under 35 U.S.C. 103 as being unpatentable over Arboleda–Velasquez (US 2020/0102384 A1, Provisional application No.62/477,289, filed on Mar. 27, 2017) in view of Yan (Pub. No.: US 2010/0129356 A1, Pub. Date: May 27, 2010).
Claim interpretation:
The specification of the claimed invention teaches that in one embodiment, the Notch-activating agent is a nucleic acid, for example a genetic construct which is delivered to target cells and expressed by such cells. The construct codes for a Notch ligand, for example, DLL1, DLL2, DLL3, DLL4, Jagged 1, Jagged 2, or variants of a Notch ligand ([0058], page 15-16). Thus, DLL1, DLL2, DLL3, DLL4 are interpreted as a Notch-activating agent.
The teachings of Arboleda–Velasquez above are incorporated herein in their entirety.
Arboleda–Velasquez does not teach Notch ligand, activator of Notch 1 or activator of Notch 4. Yan cures the deficiency.
Regarding to claims 60-63, Yan teaches methods of using a DLL4 modulator to modulate vascular development (Abstract), and “Modulators of DLL4 are molecules that modulate the activity of DLL4, e.g., agonists and antagonists. The term “DLL4 agonist' is used to refer to peptide and non-peptide analogs of DLL4 (such as the multimerized DLL4 described herein), and to other agents provided they have the ability to signal through a native Notch receptor (e.g., Notch1, Notch2, Notch3, Notch4). The term “agonist' is defined in the context of the biological role of a Notch receptor. In certain embodiments, agonists possess the biological activities of a DLL4, as defined above, such as binding a Notch receptor (e.g., Notch1, Notch2. Notch3, Notch4), activating a Notch receptor, and activating a Notch receptor downstream molecular signaling. In some embodiments, DLL4 agonists inhibit endothelial cell proliferation, promote epithelial cell differentiation, and/or promote arterial development” ([0134], page 16-17). Yan teaches “DLL4 agonists are characterized for any one or more of binding a Notch receptor (e.g., Notch1, Notch2. Notch3, Notch4), activating a Notch receptor, activating a Notch receptor downstream molecular signaling, inhibiting endothelial cell proliferation, promoting epithelial cell differentiation, and/or promoting arterial development. Methods for characterizing DLL4 antagonists and agonists are known in the art, and some are described and exemplified herein” ([0136], page 17). Yan teaches the molecules are administered to a human patient, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, or inhalation routes, and/or subcutaneous administration ([0350] page 36)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Arboleda–Velasquez by using DLL4 agonist as Notch ligand, activator of Notch 1 or activator of Notch 4 as taught by Yan to promote arterial development as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Yan teaches “methods for treating a disorder comprising administering an effective amount of a DLL4 agonist to a subject in need of such treatment. In some embodiments, the disorder is associated with expression and/or activity of the DLL4-Notch receptor pathways (such as increased activity of the DLL4-Notch receptor pathway). In some embodiments, the disorder is a disorder wherein angiogenesis, neovascularization and/or hypertrophy is desired” ([0026], page 3). Yan also teaches a method for stimulating endothelial cell proliferation in a subject in need of such treatment comprising administering an effective amount of a DLL4 agonist (see claim 6 of Yan), and treatment with DLL4 agonist increased endothelial cell proliferation both in vitro (Example 4, [0375], page 39) and in vivo (Example 5, [0376], page 39). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Yan provided detailed instructions and working example for using a DLL4 to modulate vascular development.
Claims 57, 71-73 are rejected under 35 U.S.C. 103 as being unpatentable over Arboleda–Velasquez (US 2020/0102384 A1, Provisional application No.62/477,289, filed on Mar. 27, 2017) in view of Simons et al (Pub. No.: US 2014/0120106 A1, Pub. Date: May 1, 2014).
The teachings of Arboleda–Velasquez above are incorporated herein in their entirety.
Arboleda–Velasquez does not teach ischemia of the limb; Notch-activating agent is administered by a drug eluting balloon; on a stent; the Notch-activating agent is delivered in a film wrapped around a blood vessel in the target tissue. Simons et al cure the deficiency.
Regarding to claims 57, Simons et al teach that the compositions are used to stimulate arteriogenesis or growth of lymphatic vasculature in subjects in need thereof, …… Examples of such diseases include stroke, ischemic heart failure, critical limb ischemia, angina, chronic stable angina, claudication, and lymphatic circulation deficiency ([0143], page 14).
Regarding to claims 71-72, Simons et al teach that the composition is administered locally. In these embodiments, the composition can be coated on or incorporated into a vascular device, such as a vascular graft, balloon, or stent prior to administration to a blood vessel of the subject ([0150], page 15).
Regarding to claim 73, Simons et al teach a coating, typically of a polymer, holds and elutes (releases) the drug into the arterial wall by contact transfer ([0151], page 15). Simons et al also teaches other techniques can also be used to provide controlled or sustained release at a site thereof. For example, administration in a hydrogel or other polymeric depot may be utilized ([0142], page 14).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Arboleda–Velasquez by using teaching of Simons et al to treat ischemia of the limb; to use a drug eluting balloon, on a stent, and a film wrapped around a blood vessel in the target tissue, as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Simons et al teach “polynucleotide formulation is suitable for delivery to a cell in vivo, e.g., to a cell in an organism. In another embodiment, the polynucleotide formulation is suitable for delivery to a cell in vitro, e.g., to a cell in a cell line in culture or a suspension. The polynucleotide formulation can include a ligand that is selected to improve stability, distribution or cellular uptake of the agent. For example, the ligand can be a lipophilic moiety, e.g., cholesterol, which enhances entry of the polynucleotide into a cell” ([0116], page 12). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Simons et al were successful in stimulating and controlling arteriogenesis and lymphatic vasculature with working examples and data.
Claims 75-76 are rejected under 35 U.S.C. 103 as being unpatentable over Arboleda–Velasquez (US 2020/0102384 A1, Provisional application No.62/477,289, filed on Mar. 27, 2017) in view of Colb et al (Pub. No.: US 2004/0029268 A1, Pub. Date: Feb. 12, 2004)
The teachings of Arboleda–Velasquez above are incorporated herein in their entirety.
Although Arboleda–Velasquez teach antibodies can be bispecific or monospecific ([0183], page 29). Arboleda–Velasquez do not teach binds to a ligand present in arterial cells such as CD34, Adhesion Molecule 1, or cross-linked fibrin. Colb et al cure the deficiency.
Regarding to claims 75-76, Colb et al teach endothelialization of vascular surfaces (Title): the invention involves a technique for re-endothelializing an artery whose endothelial layer has been damaged by balloon angioplasty. The technique comprises introducing into the bloodstream of a patient, prior to performing the angioplasty, a quantity of a bispecific antibody, the bispecific antibody having a first antigen binding site directed against a surface marker common to both endothelial progenitor cells (EPCs) and endothelial cells (ECs) and having a second antigen binding site directed against a subendothelial epitope (Abstract). Examples of suitable endothelial cell (EC) surface markers against which the first antigen binding site of the aforementioned multi-specific antibody may be directed include CD34 etc. ([0044], page 5)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Arboleda–Velasquez by using bispecific antibody to target endothelial cell surface marker such as CD34 as taught by Colb et al, as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Colb et al stated that “ the present invention effectively shortens the time required for re-endothelialization (and, in so doing, reduces the likelihood of neointimal thickening) by using antibodies to increase dramatically the efficiency at which circulating EPCs (and, preferably, ECs as well) are seeded onto sites of bare arterial wall.” ([0039], page 5). Colb et al teach a balloon catheter is percutaneously inserted into a peripheral artery and is then threaded through the arterial system into the narrowed coronary artery to increase the cross-sectional flow of blood through the treated coronary artery ([0005], page 1). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Colb et al were successful in re-endothelialization by using antibodies to increase the efficiency of circulating ECs are seeded onto sites of arterial wall with working examples and data.
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632