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 Request for Continued Examination filed on 07/02/2026.
Claim 1 has been amended. Claims 10, 15, 16 and 22 have been cancelled.
Claims 1-6, 8, 9, 11-14, 17, 19, 21, 23 and 24 are pending and presented for examination.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/02/2026 has been entered.
Any previous rejections and/or objections not reiterated herein have been withdrawn in view of arguments filed on 07/02/2026. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
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.
Claims 1-6, 8, 9, 11-14, 17, 19, 21, 23 and 24 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the recitation of “a pharmaceutical system comprising a microbubble-microdroplet cluster composition” renders claim 1 indefinite because it is unclear because “pharmaceutical system” is considered a product claim. However, the claim later recites method of using step “method of administering cluster composition and at least one immunotherapeutic agent” which makes it unclear. Since there is more than one interpretation for the limitation the claim is indefinite. When a claim is amenable to two or more plausible constructions, applicant is required to amend the claim to more precisely define the metes and bounds of the claimed invention, or the claim remains indefinite. A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA U.S.C. 112, second paragraph. See In re Katz Interactive call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011).
For the purpose of compact prosecution and for applying prior art, the instant claims are examined as product claims since this appears to be what claims are intended to be drawn to from the first few lines of claim 1.
The remaining 2-6, 8, 9, 11-14, 17, 19, 21, 23 and 24 claims are rejected for depending upon a rejected claim.
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, 9, 11-14, 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 Korman et al. (US 8,008,449).
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). FIG 2 shows individual clusters in size between 5 and 10 um and Table 1 states the number concentration of clusters observed in different size with variable amount of stearlyamine (0182-0183 and 0237)
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In one embodiment, if the therapeutic agent is not incorporated into the oil phase of the emulsion microdroplet, 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 (reads on first frequency), and in step iv a frequency in the range 0.05-2 MHz is preferred (reads on second frequency) (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) (reads on immunotherapeutic agent ITA), 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).
NOTE: The instant claims are examined as product claims and the administering step appears to be an intended use of the composition as recited in claim 1. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2111.02(11). In the instant case, because the composition of Healey has the identical structure and chemical composition as claimed, the composition of Healey, a contrast agent is suitable for mammalian administration imaging or controlled drug release.
Further, with respect to administering the cluster composition within 0-3 hours after mixing of the first and second component in a method of treating cancer is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal administration times in order to best achieve the desired results, such as effective treatment of the cancer and decrease of adverse effects. Further, Healey discloses that the content and size of the clusters in the cluster composition is essentially stable over some time (e.g. >1 h) after combining the first and second components in vitro, i.e. they do not spontaneously disintegrate, form larger aggregates or activates (phase shifts) spontaneously, and are essentially stable over some time after dilution, even during continued agitation. It is hence possible to detect and characterize the clusters in the cluster composition with various analytical techniques that require dilution and/or agitation (0067).Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of active agent amounts and administration times would have been obvious at the time of Applicant's invention
Healey fails to disclose at least one ITA selected from group consisting of monoclonal antibodies anti-PD1, anti-PDL1 and CTLA4 in the composition.
Korman discloses methods for using a combination immunotherapy, such as the combination of anti-CTLA-4 and anti-PD-1 antibodies, to treat hyperproliferative disease, such as cancer and methods for altering adverse events related to treatment with such antibodies individually (abstract). In one embodiment, discloses the use of anti-PD-1 antibodies and the use of combination immunotherapy, including the combination of anti-CTLA-4 and anti-PD-1 antibodies, to treat cancer and/or to decrease the incidence or magnitude of adverse events related to treatment with such antibodies individually (Col. 1 line 36-40). In one embodiment discloses compositions comprising an antibody, or antigen-binding portion thereof, or immunoconjugate or bispecific molecule, and a pharmaceutically acceptable carrier (Col. 14 line 30-35). The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof (Col. 46 line 46-50). The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems (Col. 49 line 30-34). Pharmaceutical compositions also can be administered in combination therapy, i.e., combined with other agents. For example, the combination therapy can include an anti-PD-1 antibody combined with at least one other anti-inflammatory or immunosuppressant agent (Col. 45 line 29-34). Preferred cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer) (Col. 51 line 34-41). The human anti-PD-1 antibodies can be co-administered with one or other more therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent. The antibody can be linked to the agent (as an immunocomplex) or can be administered separate from the agent, the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation (Col. 56 line 25-40). Additional disclosure includes combined PD-1 and CTLA-4 blockade may also be further combined with standard cancer treatments. For example, a combined PD-1 and CTLA-4 blockade may be effectively combined with chemotherapeutic regimes. An example of such a combination is a combination of anti-PD-1 and anti-CTLA-4 antibodies further in combination with decarbazine for the treatment of melanoma. The scientific rationale behind the combined use of PD-1 and CTLA-4 blockade with chemotherapy is that cell death, which is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway (Col. 60 line 65+).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to incorporate monoclonal antibodies PD1 or CTLA-4 into Healey’s composition. The person of ordinary skill in the art would have been motivated to make those modifications because Korman teaches that anti-CTLA-4 antibody treatment alone and anti-PD-1 antibody (Example 1) treatment alone had a modest effect on reducing tumor growth in the MC38 tumor model (e.g., FIGS. 21, 24 and 27). The anti-CTLA-4 antibody alone was quite effective in the SA1/N tumor model (FIG. 30D), which required a lower anti-CTLA-4 antibody dose for the combination studies in this model. Nonetheless, the combination treatment of anti-CTLA-4 antibody and anti-PD-1 antibody showed an unexpected, significantly greater effect on reducing tumor growth as compared to treatment with either antibody alone (e.g., FIGS. 21D, 24D, 30F and 33H-J). In addition, the results of Examples 14, 16 and 18 show that the combination treatment of anti-CTLA-4 antibody and anti-PD-1 antibody had a significant (synergistic) effect on tumor growth even at sub-optimal therapeutic doses as compared to treatment with either antibody alone (i.e., the combination therapy was surprisingly more effective at subtherapeutic doses than either monotherapy) (Col. 57 line 5-25) and reasonably would have expected success because Koraman teaches a method of altering adverse events associated with treatment of a hyperproliferative disease with an immunostimulatory therapeutic agent, comprising administering an anti-PD-1 antibody and a subtherapeutic dose of anti-CTLA-4 antibody to a subject.
Conclusion
No claims are allowed at this time.
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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/J.R.S/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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