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 .
Summary
Claims 1 - 20 are pending in this office action. All pending claims are under examination in this application.
Priority
The current application filed on January 3, 2025 claims domestic priority to provisional patent applications 63/617,652 filed on January 4, 2024 and 63/691,377, filed September 6, 2024.
Information Disclosure Statement
Receipt of the Information Disclosure Statements filed on April 3, 2026, May 6, 2026 and August 11, 2026 is acknowledged. A signed copy of the form PTO/SB/08 is attached to this office action. Note that the IDS filed May 6, 2026 is a duplicate of the one filed April 3, 2026 and has been lined through.
Specification
The disclosure is objected to because of the following informalities: the word brain appears twice in paragraph 0061.
Appropriate correction is required.
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 1-20 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.
The instant claims are directed to a method of enhancing delivery of a therapeutic agent or contrast agent through a blood-organ barrier by administering an osmotically active composition prior to administration of therapeutic agent or contrast agent. This rejection is needed because the only blood-organ barrier discussed is the blood-brain barrier (BBB).
The Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, Paragraph 1, “Written Description” Requirement, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing. This should include the following considerations: (1) actual reduction to practice, (2) disclosure of drawings or structural chemical formulas, (3) sufficient relevant identifying characteristics such as complete structure, partial structure, physical and/or chemical properties and functional characteristics when coupled with a known or disclosed correlation between function and structure, (4) method of making the claimed invention, (5) level of skill and knowledge in the art and (6) predictability of the art. For each claim drawn to a single embodiment or species, each of these factors is to be considered with regard to that embodiment or species. For each claim drawn to a genus, each of these factors is to be considered to determine whether there is disclosure of a representative number of species that would lead one skilled in the art to conclude that applicant was in possession of the claimed invention. Where skill and knowledge in the art is high adequate written description would require fewer species to be disclosed than in an art where little is known; further, more species would need to be disclosed to provide adequate written description for a highly variable genus.
First, what do the claims as a whole cover? The claims are directed to a method of enhancing delivery of therapeutic or contrast agents (hereafter collectively referred to as agents) through any blood-organ barrier via administration of an osmotically active composition.
Second, how does the scope of the claims compare to the scope of the disclosure? The specification, specifically in paragraph [0061], mentions that the invention is intended to be used for any barrier between the blood and any organ, several organs are listed including the brain. There is no further discussion of blood-organ barriers other than the BBB throughout the rest of the specification.
Third, the factors need to be considered.
(1) What was actually reduced to practice?
The method of enhancing delivery of agents by first disrupting the BBB by administration of mannitol with or without sodium chloride followed by administration of agent was actually reduced to practice.
(2) Is there disclosure of blood-organ barriers other than the BBB?
The only discussion in the specification is about the BBB, there is no information provided about any other blood-organ barrier.
(3) Are there sufficient relevant identifying characteristics disclosed?
The only identifying characteristics discussed in the specification are those of the BBB.
(4) Is there at least one method of practicing the claimed invention disclosed?
Yes, examples of opening the BBB are provided.
(5) What is the level of skill in the art and what knowledge is present in the art?
The level of skill in the art of increasing the permeability of the BBB is quite high, that of a medical doctor experience in medical research.
(6) What is the level of predictability of the art?
The level of predictability in this art is probably high. The BBB has been extensively studied and published about, the body of art regarding other blood-organ barriers is fairly sparse. The only reference found that addressed this at all is Preston et al. who teach using sodium caprate as an osmotic agent for increasing permeability of a blood-organ barrier. The abstract says, in part, The fatty acid salt, sodium caprate (C10) is a well-recognized drug absorption enhancer in intestine because of its ability to widen tight junctions in the epithelial cell lining. It is known that other barriers are formed from tight junctions in the epithelial cell lining so it seems predictable that loosening the tight junctions would make these blood-organ barriers as well as the BBB more permeable. This predictability shows that there is no lack of enablement of the claims.
It is noted that Example 1, particularly figures 5A and 5B, show improved delivery through the BBB using 25% mannitol + 4% NaCl over 25% mannitol alone. Applicant is clearly in possession of the use of mannitol with sodium chloride for disruption of the BBB via intra-arterial administration but the lack of information about other ionic osmotically active agents indicates to one skilled in the art that applicant was not in possession of the full scope of the claimed invention.
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 9 and 12 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.
Claim 9 recited that the formulation is administered intraarterially via a catheter placed in an artery that is feeding the organ or a portion thereof. Since the entire circulatory system is interconnected, any artery feeds all the organs. This claim needs further specificity.
Claim 12 recites both osmotically active agent and ionic osmotically active agent. The first term includes the latter term. Examiner suggests adding an adjective in front osmotically active agent to distinguish it from the ionic osmotically active agent.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-6, 8-11 and 17-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haluska et al.
Haluska et al. discuss treatment of brain tumors with chemotherapeutic agent preceded by BBB disruption (see figure 1) by intraarterial administration of a hypertonic solution of mannitol (25%) into a carotid or vertebral artery produces a transient and reversible disruption in the BBB by causing endothelial cell shrinkage associated with the hypertonic environment, thus opening the endothelial tight junctions.
Claims 1-3, 8-11 and 20 are taught directly.
Regarding claim 4, Haluska et al. teach administration of the therapeutic after the mannitol. No detection step is taught but the barrier disruption will have occurred before the therapeutic is administered whether it is detected or not.
Regarding claim 5, this limitation is met by the process disclosed in Haluska et al. because they clearly state that the mannitol is administered followed by the agent. The most logical way to do that would be to let go of the mannitol syringe and then pick up the agent syringe, thus, there is a stopping of the mannitol.
Regarding claim 6, the stopping discussed above would necessarily be at least one second, people can only move so fast.
Regarding claim 17, the agent is in solution.
Regarding claim 18, the diluent is water.
Regarding claim 19, Haluska et al. teach anti-cancer agents.
These teachings anticipate the above claims.
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.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Haluska et al.
The teachings of the reference are outlined above.
On page 264, rightmost column, first full paragraph says, "A femoral artery is catheterized, and a selected intracranial artery is cannulated under fluoroscopy. A solution of 25% mannitol, which osmotically opens the BBB, is infused through the catheter, followed by the intra- arterial chemotherapy. It does not say explicitly what the cannulated intracranial artery is used for.
It would have been obvious to one of ordinary skill in the art, prior to the instant effective filing date, to administer the chemo via either the femoral artery like the mannitol, or via the intracranial artery with the expectation that either would be effective to deliver the agent.
Allowable Subject Matter
Claims 12-16 are objected to as being dependent upon a rejected base claim, but would be allowable over the prior art if rewritten in independent form including all of the limitations of the base claim and any intervening claims and language that overcomes the issues under 35 USC 112.
The prior art is replete with disclosure of opening the BBB with mannitol but no teaching could be found that discusses the use of ionic osmotically active agent for the same purpose, not even along with other osmotically active agents.
Ikeda et al. teach the synergistic effect of mannitol and sodium/calcium exchange blocker on BBBO. A calcium exchanger — most commonly the sodium–calcium exchanger (Na⁺/Ca²⁺ exchanger, NCX) — is a membrane transport protein that helps regulate intracellular calcium (Ca²⁺) levels by moving calcium ions across the cell membrane in exchange for sodium ions (Na⁺). As to its mechanism: it is an antiporter, meaning it moves two different ions in opposite directions. In most cells, it exports one Ca²⁺ ion out of the cell for every three Na⁺ ions imported - this may cause one to expect a synergistic effect due to calcium or sodium ions but provides no teaching or motivation to add such salts to disrupt the BBB.
Rapoport et al. discuss calcium's role in osmotic BBB: Hypertonic exposure increases intracellular calcium concentrations in cultured cerebrovascular endothelial cells. Cytoskeletal modulation mediated by calcium also may contribute to BBB opening by hypertension, bradykinin and its synthetic analogue RMP-7, histamine, serotonin and other inflammatory response mediators and trauma, bottom of page 1810 - top of page 1811. Again, this provides insufficient motivation to add calcium salts to an osmotically active composition.
Oernbo et al. teach osmotherapy that includes intraperitoneal injection of NaCl or mannitol to reduce water levels in the brain. NaCl was slightly more efficient than mannitol as an osmotic agent. However, Oernbo et al. tested the integrity of the BBB and found that it was unchanged by the procedure, see page 11, left column, lines 6-10. Thus, there is insufficient motivation to add sodium chloride to the mannitol for disruption of the BBB. There was no disruption when administered intraperitoneally and no suggestion that there might be if administered intra-arterially.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert A. Wax whose telephone number is (571)272-0623. The examiner can normally be reached 8:00 AM -4:00 PM Monday - Friday.
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/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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