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 without traverse of i) therapeutic agent and ii) virus in the reply filed on 7/10/2025 is acknowledged.
Newly submitted claim 117 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the claim is directed to a composition comprising an adenovirus, wherein: (a) viral replication of the adenovirus is under the control of a cancer-selective promoter; and (b) the adenovirus comprises a genome encoding a melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) protein under the control of a first promoter and an imaging agent under the control of a second promoter, classified in A61K 35/76.
Claim 91 is directed to a method of administering an active agent to a target tissue in a subject, wherein the active agent is a therapeutic agent, the method comprising: (a) administering to the subject a first microbubble composition, the first microbubble composition comprising first microbubbles and not comprising the active agent; (b) a first ultrasound administration directed to the target tissue that disrupts the first microbubbles; (c) administering to the subject a second microbubble composition after the first ultrasound administration, the second microbubble composition comprising second microbubbles complexed with the active agent; and (d) a second ultrasound administration directed to the target tissue that disrupts the second microbubbles and releases the active agent to the target tissue, classified in A61K41/0047.
Accordingly, the invention of claim 117 does not require the specific components of claim 91 and vice versa, and the inventions are classified in separate classes. For example, the invention of claim 117 does not require first and second microbubbles and the invention of claim 91 does not require an adenovirus comprising (a) and (b). Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 117 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Status of Claims
Claims 91-100, 102, 103 and 110-117 are pending, of which claims 97, 98, 100, 102 and 117 are withdrawn as being directed to non-elected species or invention. Claims 91-96, 99, 103 and 110-116 encompass the elected species and are examined herein on the merits for patentability.
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) 91, 92 and 110-114 are rejected under 35 U.S.C. 103 as being unpatentable over Konofagou (US 2016/0287856).
Konofagou teaches systems and methods for opening a tissue to a target value. In an exemplary method, a region of the tissue is targeted for opening, a size range of microbubbles corresponding to the target value is determined, microbubbles of the size range are positioned in proximity to the targeted region, and an ultrasound beam is applied to the targeted region such that the tissue is opened with the assistance of the microbubbles to the target value (paragraph 0011 and abstract).
The size range of microbubbles can be 4 to 5 microns or 1 to 2 microns or 9 to 10 microns or 6 to 8 microns in some embodiments (paragraph 0013).
A method for imaging the opening of a tissue to a target permeability is also disclosed herein and includes targeting a region of the tissue for opening, determining a size range of microbubbles corresponding to the target value, positioning microbubbles of the size range in proximity to the targeted region, applying an ultrasound beam to the targeted region such that the tissue is opened with the assistance of the microbubbles to the target value, and imaging the targeted region, to form an image of the opened tissue. In some embodiments imaging the targeted region includes applying an ultrasound beam to the targeted region (paragraph 0014).
In one exemplary embodiment, the solution of microbubbles can be inserted into the subject such that the microbubbles make their way to the BBB of the subject. In one exemplary embodiment involving mice, a 25 μl bolus of the microbubble solution was injected into the tail vein of the mouse 1 minute prior to sonication. In the example of a tissue that is outside the body of a subject, the solution of microbubbles can be position in proximity to the target region by use of a syringe, or other appropriate device (paragraph 0072).
Following sonication, as described herein, the BBB opens, thereby facilitating the passage of a molecule through the BBB. Thus, a solution of contrast agent and/or other molecules (e.g., drugs) can be inserted into the subject such that it makes its way to the BBB and is able to pass through the same upon the opening of the BBB. The insertion of the molecule into the subject can occur prior to sonication, during sonication, or following sonication. Such molecule can be a drug, medication or pharmaceutical compound, protein, antibody or biological material, chemical substance, contrast agent, or any other material to pass through the BBB. In some embodiments, the molecule, whether a contrast agent, drug or other molecule, can be contained within a microbubble. In the same or another embodiment, the molecule can itself be composed of a microbubble. Further the molecule can be contained inside the microbubbles of the solution that is used to open the BBB or can itself be the same microbubbles. Such molecule can be inserted into the subject by any known method. For example, the molecule can be injected into a vein of the subject (paragraph 0073).
In one exemplary embodiment, the solution of microbubbles can be inserted into the subject such that the microbubbles make their way to the BBB of the subject. In one exemplary embodiment involving mice, a 25 μl bolus of the microbubble solution was injected into the tail vein of the mouse 1 minute prior to sonication. In the example of a tissue that is outside the body of a subject, the solution of microbubbles can be position in proximity to the target region by use of a syringe, or other appropriate device (paragraph 0072).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a first microbubble and a first ultrasound administration, followed by administration of a second microbubble complexed with an active agent and second ultrasound administration as a means of administration of a therapeutic agent in view of Konofagou. One would have been motivated to do so, with a reasonable expectation of success, because Konofagou teaches administration of a microbubble followed by sonication, thereby opening the BBB, thereby facilitating the passage of a molecule through the BBB; and that following sonication, a molecule which can be a drug, medication or pharmaceutical compound, protein, antibody or biological material, chemical substance, contrast agent, or any other material to pass through the BBB can be contained within a microbubble.
Regarding claim 92, Konofagou teaches that focused ultrasound (FUS) applied after the systemic injection of ultrasound contrast agents (UCA) can open the BBB noninvasively. This method can concurrently deliver agents to the brain through the intact skull, locally (to a targeted volume), and transiently with the BBB closing within hours of its opening (paragraph 0007). It would have been obvious to administer the therapeutic agent within the window during the time the BBB is known to be open as a matter of routine optimization of administration conditions.
Claim(s) 91-96, 99, 103 and 110-116 are rejected under 35 U.S.C. 103 as being unpatentable over Konofagou (US 2016/0287856) in view of Fisher et al. (US 2012/0195935).
The rejection over Konofagou is applied as above.
With regard to claims 93-96, 99, 103 and 116, Konofagou does not specifically recite a targeting ligand directed to tumor, wherein the active agent is a virus, or combination therapy.
Fisher teaches microbubble-assisted delivery of viruses. In particular, methods for targeting a virus to cancer cells in an immunocompetent animal by administering a selectively replicating virus to the immunocompetent animal and disrupting the microbubbles in a location of the animal comprising cancer cells are provided (abstract).
The invention provides methods of targeting a virus to cancer cells in an immunocompetent animal. In some embodiments, the method comprises administering a selectively replicating virus to the immunocompetent animal, wherein the virus is encompassed in a suspension of microbubbles, wherein the surface of the suspension does not include any virus; and disrupting the microbubbles administered to the animal in a location of the animal comprising cancer cells, wherein the virus selectively replicates in the cancer cell (paragraph 0004).
In some embodiments, the virus is an adenovirus (paragraph 0010).
The methods of the invention may be used to target a variety of diseases and tissue types. In fact, the invention can be used to treat any condition for which the virus suspended in microbubbles provides treatment, protection or amelioration. In one embodiment, the methods are used to target breast cancer, glioblastoma multiforme, etc. (paragraph 0078).
The invention further provides a method for producing a cytopathic effect in a cell comprising administering a virus in a microbubble suspension is administered, the virus is released at a desired location (e.g., by bursting the bubbles with ultrasound, and infecting the target cell(s) with a modified adenovirus according to the invention. Types of cytopathic effects include a decrease in cell proliferation, a decrease in cell metabolism, and/or cell death. The cell may be a cancer cell of for example, a nasopharyngeal tumor, a thyroid tumor, a central nervous system tumor (e.g., a neuroblastoma, astrocytoma, or glioblastoma multiforme) (paragraph 0079).
Targeting ligands on the surface of microbubbles permit the selective accumulation of these particles in the areas of interest, such as up-regulated levels of receptor/prognostic marker molecules on vascular endothelium or tumor cells (paragraph 0052).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a virus as the therapeutic agent in the methods taught by Konofagou, when the teaching of Konofagou is taken in view of Fisher. Each of Konofagou and Fisher are directed to microbubble assisted drug delivery. While Konofagou does not specifically recite a virus as the therapeutic agent which is delivered to brain, one would have been motivated to do so, with a reasonable expectation of success, because Fisher teaches a virus to be suitable for encapsulation in a microbubble for treatment of tumor, including glioblastoma multiforme (brain). It would have been further obvious to provide a targeting ligand as taught by Fisher for site specific delivery to tumor.
Regarding claim 103, a combination of two or more Terminator or Triage Viruses suspended in microbubbles may be used for a method of treatment of a cancer or other disease state. In this embodiment two or more Terminator or Triage Viruses expressing distinct genes of interest may be used in combination (administered concurrently or sequentially) for treatment in a human or non-human animal subject (paragraph 0084), accordingly, it would have been obvious to provide an additional therapeutic administration and ultrasonic pulse for administration thereof.
Regarding claim 115, it would have been further obvious to administer another anticancer agent that is not contained within microbubbles because Fisher teaches that combination therapy includes but is not limited to simultaneous or serial treatment with a Terminator or Triage Virus embodied in instant invention and standard radiotherapy or chemotherapy regimes. Chemotherapy may include but is not limited to treatment with appropriate doses of chemotherapy agents such as Cisplatin, Adriamycin, Doxorubicin, Paclitaxel or other Taxol derivatives, etc. In an additional embodiment, specific targeting to an organ, tumor or tissue type or enhanced infectivity is obtained by utilizing an appropriate Triage Virus (paragraph 0083).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL HARTLEY 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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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618