DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09 April 2026 has been entered.
This Office Action is in response to Applicant’s Amendment and Remarks filed on 09 April 2026 in which claims 3, 7, 8, 11, 12, 16, 17, 20, and 21 were canceled, claims 1, 5, 6, 14 and 15 were amended to change the scope and breadth of the claims, and claim 22 was newly added.
Claims 1, 2, 4-6, 14, 15, 18, 19 and 22 are pending in the current application and are examined on the merits herein.
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 .
Withdrawn Rejections
Applicant’s amendment, filed 09 April 2026, with respect to the rejection of claims 5, 6, 11, 12, 14, 20 and 21 under 35 U.S.C. § 103 as being unpatentable over Lee et al. in view of Zhang et al. has been fully considered and is persuasive because claim 5 has been amended to depend from claim 1, and claim 1 has been amended to recite “wherein the chemically modified heparin…and hydrophobic moieties attached to at most 10% of functional groups of the heparin”.
Lee et al. do not specify the degree of substitution of the heparin. The rejection is hereby withdrawn.
New & Modified Rejections
The following are new ground(s) or modified rejections.
Claim Interpretation
Claim 1 recites “wherein the nanoparticle has a size in the range of from 40 nm to 200 nm and consists of chemically modified heparin…wherein said nanoparticle is not attached to a cytotoxin and wherein the nanoparticle is free of arginylglycylaspartic acid (RGD) peptides” in claim 1 expressly excludes a nanoparticle having any additional components, e.g. doxorubicin, dopamine, gallic acid, or a metal core as recited in claims 5 and 22.
The term “consists of” expressly limits the nanoparticle, and everything encompassed by the nanoparticle, not simply the heparin as argued by Applicant. If only the heparin were limited, the claim would recite “a nanoparticle comprising heparin, wherein the heparin consists of…”. Such a claim would then allow for loaded doxorubicin (as this is physical loading, and not chemical attachment). Such a claim would also allow for a metal core.
Claim 1 also expressly excludes heparin chemically modified with a cytotoxin, and excludes RGD peptides.
Response to Arguments
Applicant's arguments, filed 09 April 2026, with respect to the rejection under 35 U.S.C. §112(a), first paragraph, have been fully considered but they are not persuasive.
Applicant contends the specification provides a clear and repeatable protocol for chemically modifying heparin using EDC/HOBT coupling, where the specific label/hydrophobic group is fluorescein-5-thiosemicarbazide (FTSC). Applicant argues the “predictability” inquiry must focus on the making and using of the structure, not necessarily the predictability of therapeutic success relative to failed prior art.
The above arguments are not found persuasive. The using of the structure in the present claims is “treatment of diagnosis of brain disorders”. In this particular art, nanoparticles consisting of heparin conjugated to hydrophobic groups have been prepared, and when these particles are “blank”, i.e. do not encompass a cytotoxic drug, or a metal oxide core, they have not been found to be effective in treating brain disorders as required by the present claims.
Applicant argues Mei et al. and Sun et al. are directed to heparin derivatives having molecular weights and/or a degree of substitution that differ from the claimed ranges. Applicant notes the present claims require the degree of chemical modification is limited to “at most 10%”, and require a molar mass of at least 8 kDa. While Applicant has provided a theory as to why prior art groups were unsuccessful in treating brain cancer with heparin nanoparticles, there is no evidence that would allow the skilled artisan to extrapolate the data in the present Specification to other heparin nanoparticles with different hydrophobic groups. There is insufficient data to show the degree of substitution and MW are critical to achieving the claimed therapeutic effect.
Applicant even acknowledges the claimed method is unexpected in light of the prior art.
Applicant argues “A person of skill would have expected a peptide-free particle (like the one claimed) to be cleared by the reticuloendothelial system or to remain sequestered on the blood side of the BBB” (see page 10 of the Remarks submitted 09 April 2026).
Applicant argues “The finding that removing both the targeting ligand (RGD) and the anti-tumour drug (Doxorubicin) results in a more effective treatment for glioblastoma is an outcome that is “different in kind” from anything taught in Zhang or Lee. It contradicts the foundational assumption of nanomedicine that complex cargo-loading and ligand-decoration are necessary for CNS efficacy”.
Applicant argues “In making the rejection, Examiner cites the lack of cytotoxicity in the “blank” heparin particles of Mei et al. and Sun et al. as a reason why the Applicant’s result is unpredictable. This reasoning is circular: if the result were predictable, the Examiner would reject it as obvious; because it is unpredictable, the Examiner rejects it as not enabled”.
However, MPEP 2145, states “For example, a showing of unexpected results for a single member of a claimed subgenus, or a narrow portion of a claimed range would be sufficient to rebut a prima facie case of obviousness if a skilled artisan "could ascertain a trend in the exemplified data that would allow him to reasonably extend the probative value thereof."
Applicant should note the rejection under 35 U.S.C. §112(a), is a scope of enablement rejection. Meaning, there is insufficient evidence to show Applicant’s full scope of compounds encompassed by the present claims are fully enabled for the claimed use of treating and diagnosing a subject with a brain tumor. The data provided by the prior art as a whole and the Specification show the results presented in the Specification appear to be unexpected. However, it is not clear if the results presented therein could be extended to other compounds encompassed by the present claims. Applicant’s data in the present Specification for a “blank” heparin particle are limited to a single nanoparticle having a single hydrophobic moiety.
Currently, there is insufficient evidence that the data pertaining to a heparin-fluoresceine conjugate could be extrapolated to any hydrophobic moiety, with a reasonable expectation of success in treating any brain disorder in a mammal having a brain tumor.
To overcome the rejection over claim 1, the claim could be amended to require the hydrophobic moiety is a fluorescein.
Alternatively, Applicant could provide additional evidence showing enablement for other species of hydrophobic moieties encompassed by the claims.
The rejection is hereby maintained.
Claim Rejections - 35 USC § 112(a), New Matter
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, 2, 4-6, 14, 15, 18, 19 and 22 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.
Applicant’s amendment with respect to the amended claim 1 has been fully considered but is deemed to insert new matter into the claims since the specification as originally filed does not provide support for the particular genus of compounds encompassed/excluded by “cytotoxin” in the present claimed method.
The specification as originally filed merely discloses doxorubicin, cisplatin or temozolomid as species of the subgenus compounds of anticancer agents/anti-tumor agents (see para [0105]). The specification only discloses doxorubicin also functions as having cytotoxic properties (see para [0200]). Furthermore, while anticancer/anti-tumor agents function as cytotoxic agents, cytotoxic agents do not necessarily function as anti-tumor agents. There are no disclosed examples of compounds that are cytotoxic agents and not anti-tumor agents. The specification fails to disclose the particular genus of cytotoxins, and the various members of that class of compounds.
Thus, the specification as originally filed does not support the method of treatment or diagnosis of brain disorders in a mammal by administering heparin not attached to a cytotoxin.
As noted in MPEP 2163, “a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads”, see In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972).
The court of In re Curtis held that “a patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when… the evidence indicates ordinary artisans could not predict the operability …..of any other species.” (see In re Curtis 354 F.3d 1347, 69 USPQ2d 1274, Fed. Cir. 2004). The court of Noelle v. Lederman also pointed out that generic claim to anti-CD40CR Mabs lacked written description support because there was no description of anti-human or other species Mabs, an no description of human CD40CR antigen. The court further pointed out that attempt to “define an unknown by its binding affinity to another unknown” failed. See 355 F.3d 1343, 69 USPQ2d 1508, Fed. Cir. 2004.
Consequently, there is nothing within the instant specification which would lead the artisan in the field to believe that Applicant was in possession of the invention as it is now claimed. See Vas-Cath Inc. v. Mahurkar, 19 USPQ 2d 1111, CAFC 1991, see also In re Winkhaus, 188 USPQ 129, CCPA 1975.
Claim Rejections - 35 USC § 112(a)
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, 2, 4, 5-8, 14, 15, 18, 19 and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a brain tumor with heparin chemically modified with fluorescein (having a molar mass of 8-30 kDa, and at most 10% of functionalization), does not reasonably provide enablement for treating any brain disorder with heparin chemically modified with any hydrophobic moiety (of any molecular weight, or any degree of modification). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
The nature of the invention:
The nature of the invention is the use of blank heparin nanoparticles (i.e. self-assembled heparin NPs, not containing a cytotoxin or RGD peptide).
The state of the prior art:
Mei et al. (ACS Appl. Mater. Interfaces, 2016, vol. 8, p.9577-9589, cited in previous Office Action) teach preparing heparin nanoparticles, wherein the heparin is chemically modified with a hydrophobic group. The hydrophobic group is deoxycholate. Mei et al. found heparin-deoxycholate (compound 3, referred to as HD) was not cytotoxic towards B16F10 cells (murine melanoma cells) or MDA-MB-231 cells (breast cancer cell line), (fig. 5A, 5B; p.9582, 3.3).
Sun et al. (International Journal of Biological Macromolecules, 2018, vol. 112, pp. 343-355, cited in previous Office Action) teach preparing heparin nanoparticles, wherein the heparin is chemically modified with a hydrophobic group. The hydrophobic group is cholesterol. Sun et al. found blank LMW heparin chemically modified with cholesterol was not cytotoxic towards 4T1 breast cancer cells (p.347, 3.4.).
Li et al. (Macromolecular Research, 2011, vol. 19, no. 5, pp. 487-494, cited in previous Office Action) teach preparing heparin nanoparticles, wherein the heparin is chemically modified with a hydrophobic polymer. The hydrophobic polymer is poly-(β-benzyl-L-aspartate), PBLA. The HP-NPs cytotoxicity towards mouse squamous carcinoma cell line SCC7 was tested (p.489, In Vitro Phototoxicity Test). While Li et al. teach loading the nanoparticles with pheophorbide a, a photosensitizer (to give HP-Pheo), they found the NPs were not cytotoxic unless light was applied (p.493, In Vitro Phototoxicity and Cellular Uptake Tests). Li et al. specifically teach “Without light treatment, the viability of cells treated with 6HP-Pheo15 and 6HP-Pheo20 was in the range of 82-103% even at high nanoparticle concentrations. These results indicate that Pheo-loaded HP nanoparticles not only have marked photokilling effectiveness but also be non-toxic to the cell lines until the treatment is applied”.
The predictability or unpredictability of the art:
Mei et al., Sun et al. and Li et al. teach preparing heparin nanoparticles, wherein the heparin NPs are chemically modified with a hydrophobic group. These hydrophobic groups include deoxycholate, cholesterol and poly-(β-benzyl-L-aspartate). Mei et al. and Sun et al. expressly found blank heparin NPs were not cytotoxic towards the cancerous cell under investigation. And Li et al. found photosensitizer loaded heparin NPs were not cytotoxic towards the cancerous cell under investigation unless light was applied.
From these prior art references, it would seem heparin nanoparticles, wherein heparin is chemically modified with certain hydrophobic moieties are not cytotoxic towards cancerous cells.
The relative skill of those in the art: The relative skill of those in the art was high. Modifying heparin with hydrophobic groups so they will self-assemble into nanoparticles was known, loading them with cytotoxic drugs was known, and using these nanoparticles to treat various cancers was known at the time of the effective filing date.
The breadth of the claims: The breadth of the claim 1 includes heparin chemically modified with any hydrophobic group. The breadth of claim 2 includes cholesterol and hydrophobic polymers, which wherein the prior art references found they were not cytotoxic without an anti-tumor agent or light. The breadth of the claims also includes additional hydrophobic groups including ceramides, fatty acids, PLGA, poloxamers and hydrophobic monomers.
The breadth of the claims also includes treating any brain disorder, including cognitive decline.
The amount of direction or guidance presented/The presence or absence of working examples:
Example 1 of the Specification describes preparing a heparin nanoparticle, wherein the heparin is chemically modified with fluorescein.
In an in vivo glioma model, heparin nanoparticles from example 1 were administered (p.34-35 Specification). As seen in figure 18B, the tumor volume from blank heparin NPs was significantly better than for the nanoparticles having doxorubicin.
The quantity of experimentation necessary: In order to practice the invention with the full range of all possible treatment methods beyond those known in the art, one skilled in the art would undertake a novel and extensive research program to show that the full scope of hydrophobically modified heparin NPs could be useful to treat glioma.
In order to determine the efficacy of the claimed therapies in the absence of any existing in vivo data, one skilled in the art would undertake animal testing in order to practice the invention. Animal experiments include, induction of the disease state, administration of the potential pharmaceutical compound and collection and analysis of data, additional burdens associated with compliance with animal welfare regulations, care, feeding and other maintenance of the animals, dissection of dead animals to collect data, and dispose of the dead animals after the research is finished. These trials would need to be run separately and repeatedly for each disorder to be treated, and success in treating each and every disorder would still not be definitive. The experimentation involved would therefore be significant, undue and unpredictable.
Genentech, 108 F.3d at 1366, sates that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors, as discussed above, particularly the breadth of the claims, Applicants fail to provide information sufficient to practice the claimed invention for treating a brain tumor with heparin chemically modified with any hydrophobic moiety.
Response to Arguments
Applicant's arguments filed 09 April 2026 have been fully considered but they are not persuasive.
With respect to the use of “consists of”, Applicant argues the term is designed to exclude complex surfactants and peptide targeting ligands of the prior art.
The arguments are not found persuasive. Claim 1 express recites “wherein the nanoparticle has a size in the range of from 40 nm to 200 nm and consists of chemically modified heparin, wherein the chemically modified heparin has a molar mass of at least 8 kDa and hydrophobic moieties attached to at most 10% of functional groups of the heparin”.
Any additional components whether provided as a mixture, a coating, a core, or covalent conjugation are expressly excluded from claim 1. This interpretation is consistent with MPEP 2111.03(II), “The transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim.”.
If Applicant wishes to exclude other polymers, peptides or drugs, or exclude RGD-IONPs, or drug-loaded micelles, Applicant may expressly exclude those from the claim, if there is support in the present Specification.
To overcome the rejection over claims 5, 6, 18, 19 and 22, these claims could be rewritten as independent claims.
The rejections under 35 USC §112(b) and 35 USC §112(b) are hereby maintained.
Claim Rejections - 35 USC § 112(b)
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 5, 6, 18, 19 and 22 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.
The recitation “wherein the nanoparticle is chemically or physically attached…” in claim 18 lacks antecedent basis. Claim 1 recites “wherein the nanoparticle…consists of chemically modified heparin, wherein the chemically modified heparin has a molar mass of at least 8 kDa and hydrophobic moieties attached to at most 10% of functional groups of the heparin”. Claim 1 is interpreted as limited to heparin chemically attached to hydrophobic moieties. Thus, heparin or nanoparticle cannot further be modified to include “a nucleic acid, an antibody, a peptide or a protein, or to a diagnostic agent” as recited in claims 18 and 19.
The same rational applies to claims 5, 6 and 22.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5, 6, 18, 19 and 22 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The recitation “wherein the nanoparticle is chemically or physically attached…” in claim 18 fails to further limit the subject matter of the claim upon which it depends. Claim 1 is interpreted as limited to heparin chemically attached to hydrophobic moieties. Thus, heparin further functionalized with a nucleic acid, antibody, peptide, protein or diagnostic agent results in a heparin structure that fails to further limit the structure of heparin from independent claim 1.
The same rational applies to claims 5, 6 and 22.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The rejection is hereby maintained.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAHAR A CRAIGO whose telephone number is (571)270-1326. The examiner can normally be reached M-F: Noon-8pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Fereydoun Sajjadi can be reached at 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699
Prosecution Insights