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 .
Receipt is acknowledged of Applicant’s Amendments and Arguments filed on 12/11/2025.
Claims 1-6, 8-14, 17-19, 21, 23 and 24 have been amended. Claims 15, 16 and 22 have been cancelled. Accordingly, claims 1-6, 8-14, 17,19, 21, 23 and 24 are pending and presented for examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/11/2025 was noted and the submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Any previous rejections and/or objections not reiterated herein have been withdrawn in view of amendments. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Claim(s) 1-6, 8-17, 19, 21, 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Healey et al. (US 2016/0243234) in view of Fahmy et al. (US 2018/0200196) and Manekas et al. (US 10,544,224).
Healey discloses a cluster composition and a pharmaceutical composition, and their use for delivery of therapeutic agents, a contrast agent for ultrasound imaging, methods for delivering such therapeutic agents and suitable for mammalian administration (abstract and 0080). The delivery of therapeutic agents/drugs include the delivery of drug molecules, nanoparticles and nanoparticle delivery systems (0032). In one embodiment discloses a cluster composition that comprises a suspension of clusters in an aqueous biocompatible medium, where said clusters have a diameter in the range of 1 to 10 µm, and a circularity <0.9 and comprise: (i) a first component which comprises a gas microbubble and first stabilizer to stabilize said microbubble; and (ii) a second component which comprises a microdroplet comprising an oil phase and second stabilizer to stabilize said microdroplet, where said second component optionally further comprises a first therapeutic agent; where the microbubbles and microdroplets of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions (0062-0065). In one embodiment, if the therapeutic agent is not incorporated into the oil phase of the emulsion microdroplet, the therapeutic agent can be separately administered, such as being co-administered or pre-administered or post-administered with the cluster composition (0080). In one embodiment, the invention provides a method for delivery of drugs as part of a multi-drug treatment regime (0103). In one embodiment, provides a pharmaceutical composition that comprises (i) the cluster composition as defined in the first aspect (ii) an optional second therapeutic agent, provided either in mixture with (i), or as a separate composition to (i) (0113-0116). In one embodiment discloses a method of delivering at least one therapeutic agent to the mammalian subject, comprising the steps of: (i) administering the pharmaceutical composition (ii) optionally imaging the microbubbles of said pharmaceutical composition using ultrasound imaging to identify the region of interest for treatment within said subject; (iii) activating a phase shift of the diffusible component of the second component of the cluster composition from step (i) by ultrasound irradiation of a region of interest within said subject, such that: (a) the microbubbles of said clusters are enlarged by said diffusible component of step (iii) to give enlarged bubbles which are localized at said region of interest due to temporary blocking of the microcirculation at said region of interest by said enlarged bubbles; and (b) said activation of step (iii) facilitates extravasation of the therapeutic agent(s) administered in step (i), (iv) optionally, facilitating further extravasation of the therapeutic agent(s) administered in step (i) by further ultrasound irradiation. In in steps ii, iii and iv, ultrasound of any mechanical index (MI) may be used. However, in step ii a MI of <0.15 is preferred, and in steps iii and iv a MI of <0.7 is preferred. In this context, in steps ii, iii and iv, ultrasound of any frequency between 0.05 to 30 MHz may be used. . In steps ii and iii a frequency in the range of 1-10 MHz is preferred, and in step iv a frequency in the range 0.05-2 MHz is preferred (0120-0127). Activation of the cluster composition was performed with an additional transducer (either the Vivid E9 or Vscan) for 75 seconds starting from the time of injection of the cluster composition (0309). In one embodiment the first component containing microbubbles comprises dispersed gas and material to stabilize said gas. The gas includes sulphur hexafluoride, and biocompatible halogenated hydrocarbon gases such as perfluorinated gases and the oil phase of the microdroplet of the second component comprises a partly halogenated hydrocarbon, a fully halogenated hydrocarbon or a mixture thereof, the first stabilizer and the second stabilizer each independently comprises a phospholipid, a protein, a polymer a polyethylene glycol, a fatty acid, a positively and negatively charged surfactant, or mixture thereof (0081 and claim 1-5). Therapeutic agents include genes (for gene therapy), chemotherapeutics, immunotherapeutic (e.g. for cancer therapy or organ transplant therapy), angiogenesis producing drugs for example to stimulate the growth of new blood vessels, drugs to pass the blood brain barrier for example to treat cancer or neurological diseases (0095) and chemotherapeutic drugs include alkylating agents, kinase inhibitor (bortezomib), monoclonal antibodies (bevacizumab), and nucleotide analogs and precursor analogs(0096). These formulations retain the critical attributes of the concept in the formation clusters in the cluster composition, their ability to be activated upon insonation and the lack of spontaneous activation (0293). Additional disclosure includes that, the volume of an activated bubble from the current invention is typically 1000 times that of a regular microbubble. At equal MI, insonated at a frequency close to resonance for both bubble types (0.5 MHz for phase shift microbubbles and 5 MHz for regular contrast agent microbubbles) it has been shown that the absolute volume displacement during oscillations are almost three orders of magnitude larger with the phase shift bubbles than with a regular contrast microbubble. Hence, insonation of phase shift bubbles will produce completely different levels of bio-mechanical effects, with significantly larger effect size and penetration depth than during insonation of regular contrast microbubbles. The larger phase shift bubbles can be oscillated in a softer manner (lower MI, e.g. <0.4), avoiding cavitation mechanisms, but still inducing sufficient mechanical work to enhance the uptake of drug from the vasculature and into the target tissue (see Example 8) (0077).
Healey fails to disclose at least one ITA selected from group consisting of monoclonal antibodies anti-PD1, anti-PDL1 and CTLA4 in the composition.
Fahmy discloses nanoparticulate compositions typically include at least one, two or more, active agent(s), one of which is an immunomodulatory compound, loaded into, attached to the surface of and/or enclosed within a delivery vehicle. The delivery vehicles can be nanolipogels including a polymeric core and a lipid shell or a biodegradable polymeric nanoparticle such as a PLGA nanoparticle. Methods of using the compositions to enhance an immune response and treat diseases such as cancer are also disclosed (abstract). In one embodiment, the nanoparticulate composition includes nanolipogels or other polymeric particles having a proinflammatory cytokine and the additional active
agent is an immune modulator or a chemotherapeutic agent. The one or more active agents is an immune response stimulator or enhancer such as a PD-1 antagonist (e.g., antagonistic anti-PD1 antibody, anti-B7-H1 antibody, etc.), or a CTLA4 antagonist (e.g., antagonistic anti-CTLA4 antibody), or even more preferably a combination thereof (0016).The active agents is a proinflammatory chemokine, a family of small cytokines. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells. Therefore, they are chemotactic cytokines. Proteins are classified as chemokines according to shared structural characteristics such as small size (they are all approximately 8-10 kilodaltons in size (0119). Additional disclosure includes that the method can be used to treat a subject in whom an enhanced immune response (e.g, an increase or induction of T cell responses such as T cell proliferation or activation) is desired. Exemplary subjects include those with cancer or an infectious disease. The immune response can be effective to treat the cancer or infection. In some embodiments, the immune response is against cancerous and/or disease infected cells and can reduce one or more symptoms of the cancer and/or disease (e.g., tumor burden, tumor progression, disease progression, etc.) and treatment regimens are also provided (0017).
Manekas discloses pharmaceutical compositions and method for treating HPV-positive squamous cell carcinoma of the head and neck comprising administering to the subject an immune checkpoint inhibitor, e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody (abstract). In certain embodiments, the method further comprises administering one or more additional anti-cancer agents. In one particular embodiment, the anti-cancer agent is selected from the group consisting of an antibody or antigen-binding portion thereof that binds specifically to a CTLA-4 and inhibits CTLA-4 activity, a chemotherapy, a platinum-based doublet chemotherapy, a tyrosine kinase inhibitor, an anti-VEGF inhibitor, or any combination thereof (Col.2 line 48-55). Manekas discloses that the therapy of the invention effectively increases the duration of progression free survival of the subject. For example, the progression free survival of the subject is increased by at least about 2 weeks, at least about 1 month, or at least about 1 year when compared to another subject treated with only standard-of-care therapy. In certain embodiments, after the administration of an anti-PD-1 antibody or anti-PD-L1 antibody therapy, the subject exhibits an overall response rate of at least about 30%, 35%, 36%, 37%, 39%, 40%, 45%, or 50% compared to the response rate after administration of a standard-of-care therapy (Col. 17 line 5-35). Additional disclosure includes that the anti-PD-1 antibody is administered in combination with any chemotherapy known in the art.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to incorporate at least one of antibodies anti-PD-1, anti-PDL-1 or CTLA4 into Healey’s composition. The person of ordinary skill in the art would have been motivated to make those modifications because Fahmy teaches that when one or more chemotherapeutic agents such as doxorubicin is co-administered in combination with nanolipogcls or particles loaded or associated with a proinflammatory cytokine, (1) the chemotherapeutic agent(s) can be administered at a lower dose; (2) the chemotherapeutic agent(s) will exhibit reduced side effects or toxicity to the subject; (3) the chemotherapeutic agent will exhibit enhanced potency, and/or (4) the result achieved by the chemotherapeutic agent in combination with the loaded nanolipogels or particles will have a greater than additive effect on the subject when compared to administered the chemotherapeutic agent(s) without the loaded nanolipogels or particles; or administering the loaded nanolipogels or particles in the absence of the chemotherapeutic agent(s) and reasonably would have expected success because administration of Fahmy’s composition increases an immune response, destroy cancer cells, interfere with cancer growth and/or metastasis, and/or reduce one or more adverse consequences and/or sequelae of the cancer.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to incorporate at least one of antibodies anti-PD-1, anti-PDL-1 or CTLA4 into Healey’s composition. The person of ordinary skill in the art would have been motivated to make those modifications because Manekas teaches that the anti-CTLA-4 antibodies useful for the combination can bind to human CTLA-4 so as to disrupt the interaction of CTLA-4 with a human B7 receptor. Because the interaction of CTLA-4 with B7 transduces a signal leading to inactivation of T-cells bearing the CTLA-4 receptor, disruption of the interaction effectively induces, enhances or prolongs the activation of such T cells, thereby inducing, enhancing or prolonging an immune response (Col. 22 line 35-45) and reasonably would have expected success because Manekas teaches that after the administration of an anti-PD-1 antibody or anti-PD-L1 antibody therapy, the subject exhibits an overall response rate of at least about 30%, 35%, 36%, 37%, 39%, 40%, 45%, or 50% compared to the response rate after administration of a standard-of-care therapy (Col. 17 line 5-35).
Response to Applicant Arguments
Applicant argues that ordinary artisan reading Fahmy would not be motivated to select the recited specific group of immunoactive agents, combine this with the teaching of Healey, and further optimize the method of include a specific ultrasound-mediated delivery regime suitable for the immunotherapeutic agents.
This argument is not persuasive since the motivation to combine the references does not necessarily have to match with what applicant wants to accomplish. The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991). In the instant case, Healey reference discloses a cluster composition and a pharmaceutical composition, and their use for delivery of therapeutic agents, a contrast agent for ultrasound imaging, methods for delivering such therapeutic agents and suitable for mammalian administration (abstract and 0080). The delivery of therapeutic agents/drugs include the delivery of drug molecules, nanoparticles and nanoparticle delivery systems (0032) and a cluster composition that comprises (i) a first component which comprises a gas microbubble and first stabilizer to stabilize said microbubble; and (ii) a second component which comprises a microdroplet comprising an oil phase and second stabilizer to stabilize said microdroplet, where said second component optionally further comprises a first therapeutic agent; where the microbubbles and microdroplets of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions (0062-0065). And activating a phase shift of the diffusible component of the second component of the cluster composition by ultrasound irradiation, to facilitates extravasation of the therapeutic agent(s) administered while Fahmy reference is relied upon to show nanoparticulate compositions typically including at least one, two or more, active agent(s), one of which is an immunomodulatory compound, loaded into, attached to the surface of and/or enclosed within a delivery vehicle. One or more active agents is an immune response stimulator or enhancer such as a PD-1 antagonist (e.g., antagonistic anti-PD1 antibody, anti-B7-H1 antibody, etc.), or a CTLA4 antagonist (e.g., antagonistic anti-CTLA4 antibody), or even more preferably a combination thereof (0016).
Note: With respect to administration of immunotherapeutic agents pre and/or co- an/or post administered limitation would have been obvious to one of ordinary skill in the art by varying the amount of the composition or dosage, the administration protocol can be optimized based on the present disclosure to elicit a maximal improvement in symptoms. Physicians, pharmacologists, and other skilled artisans are able to determine the most therapeutically effective treatment regimen, which will vary from patient to patient. The potency of a specific composition and its duration of action can require administration on an infrequent basis, including co-administrating sequentially or simultaneously that have desirable pharmacokinetic characteristics and desirable attributes. Those of ordinary skill in the art can readily optimize effective doses and administration regimens as determined by good medical practice and the clinical condition of the individual patient. As disclosed by Manekas, the anti-PD-1 antibody or anti-PD-L1 antibody is administered in combination with the standard of care for the particular typed of cancer and the anti-PD-1 antibody or anti-PDL-1 antibody is administered before, concurrently or after radiation therapy or after surgical resection (Col.28-line 65+). Regardless of the manner of administration, it can be appreciated that the actual preferred amounts of therapeutic agent in a specific case can vary according to the particular therapeutic agent and the route of administration.
Conclusion
No claims are allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGADISHWAR RAO SAMALA whose telephone number is (571)272-9927. The examiner can normally be reached Monday-Friday 9am-6pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Hartley G Michael can be reached at 571 272 0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.R.S/ Examiner, Art Unit 1618
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618