DETAILED ACTION
Applicants’ arguments, filed 29 July 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 1-5, 7-10, 12-13, 16-20, 22-23, and 95-96 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.
Claim 1 has been amended in the following manner, which is reproduced below with annotation by the examiner.
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The newly added phrase “comprising no therapeutically active material” does not appear to be adequately supported by the original application as filed. The examiner reviewed the text of the originally filed specification and the phrase “therapeutically active” does not appear to have been presented therein. As such, the above-indicated newly added phrase does not appear to have been presented in the originally filed application and would appear to be new matter.
The examiner notes that claim amendments intended to address this new matter rejection may prompt the examiner to reconsider prior art rejections which have been withdrawn.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
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 1-5, 7-10, 12-13, 16-20, 22-23, and 95-96 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 1 has been amended in the following manner, which is reproduced below with annotation by the examiner.
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As such, claim 1 has been amended to exclude a therapeutically active material. However, claim 13 recites that the nanoparticle is conjugated to a DNase I inhibitor. The skilled artisan may have understood a DNase I inhibitor to have been a therapeutically active material because a DNase I inhibitor is useful for the therapeutic goal of increasing the concentration of cell-free DNA by preventing said DNA from being degraded. As such, it is unclear if claim 1 excludes or does not exclude a therapeutically active material.
For the purposes of examination under prior art, the examiner will proceed in examination with the understanding that claim 1 excludes all therapeutic agents that are not targeting agents. Indefinite claim 13 will be interpreted with the understanding that it has the same scope as claim 1. Potential claim amendments to address this issue may not be entered after-final to the extent that such amendments may require the examiner to search the full scope of drugs in order to determine which drugs would inherently have had DNAse I inhibitory activity – this would appear to be an area of new search and consideration that would prompt non-entry after-final.
Claim Interpretation
For the purposes of examination under prior art, the examiner understands that the Kupffer cell targeting moiety of claim 96 is not a therapeutically active material because it is a targeting moiety.
Additionally, while the claims are understood to exclude therapeutically active materials that are part of the nanoparticle, they are not understood to exclude therapeutically active materials that are administered separately from the nanoparticle (e.g. in a separate injection).
Claim 1 recites “a subject in need thereof.” Claim 22 further limits the patient population to be drawn to human patients who have, are suspected of having, or are at risk for a disease associated with the presence of cell-free DNA, which may include cancer. As best understood by the examiner, every human who does not already have cancer is at risk for having cancer. As such, the examiner best understands the patient population of “a subject in need thereof” to be drawn to all humans because all humans are at risk for having cancer.
Withdrawn Rejections
In the prior office action mailed on 30 April 2026, the examiner previously rejected the instant claims under 35 U.S.C. 112(a) as lacking enablement. This rejection has been withdrawn in view of the claim amendment limiting the nanoparticle to having a zeta potential from -200 mV to 0 mV and excluding particles with a positive zeta potential.
In the prior office action, the examiner rejected the instant claims as being anticipated by and/or obvious over Du Clos et al. (Clinical and Experimental Immunology, Vol. 117, 1999, pages 403-411) and/or Zeisberger et al. (British Journal of Cancer, Vol. 95, 2006, pages 272-281). These rejections have been withdrawn in view of the claim amendment excluding therapeutically active material. This is because both Du Clos and Zeisberger teach that the administered nanoparticles comprise clodronate. Clodronate is excluded by the newly added claim limitation excluding therapeutically active material. As such, the previously applied rejections over Du Clos and/or Zeisberger, by themselves or in combination with other references, have been withdrawn in view of this newly added claim limitation.
The examiner takes the position that withdrawal of these rejections should not imply agreement with every statement made in applicant’s response on 29 July 2026.
Claim Rejections - 35 USC § 103 – Obviousness
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5, 7-10, 12-13, 16-20, 22-23, and 95-96 is/are rejected under 35 U.S.C. 103 as being unpatentable over Germain et al. (US 2017/0258717 A1) in view of Moghimi et al. (Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 11(1), 1994, pages 31-59).
Germain et al. (hereafter referred to as Germain) is drawn to administration of at least two distinct biocompatible nanoparticles as well as a compound of interest, as of Germain, title and abstract. Particles are sized from about 4 nm to about 500 nm, as of Germain, abstract, and may have a negative zeta potential more negative than -10 mV, as of Germain, paragraphs 0030-0031, which is -25 mV in paragraph 0089.
For the purposes of this rejection, the examiner takes the position that Germain does not clearly teach that the nanoparticles referred to as biocompatible nanoparticles lack therapeutically active material.
Moghimi et al. (hereafter referred to as Moghimi) is drawn to avoiding particle clearance from blood by Kupffer cells, as of Mohimi, page 31, title and abstract. Moghimi teaches the following, as of page 35, relevant text reproduced below.
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As such, Moghimi teaches administration of empty drug carriers prior to administration of test particles to reduce Kupffer cell uptake.
Moghimi does not clearly indicate that the empty drug carriers are nanoparticles having a zeta potential in the claimed range.
It would have been prima facie obvious for one of ordinary skill in the art to have modified Germain to have administered empty nanoparticles. Germain specifically cites the Moghimi publication as of paragraph 0012 of Germain, to suggest administration of empty particles prior to administration of a test particle to reduce Kupffer cell uptake. As such, the skilled artisan would have been motivated to have modified the method of Germain such as to render the biocompatible nanoparticles of Germain to be empty in order to have predictably reduced Kupffer cell uptake of a test particle or a particle with an active agent with a reasonable expectation of success.
As to claim 1, the claim is drawn to a method for increasing the concentration of cell-free DNA, and requires that the method results in increased concentration of cell-free DNA in one or more biological fluids of the subject. The skilled artisan would have expected that the method of administration of empty particles would have done this even if it was not recognized by Germain or Moghimi. This is at least because the experiments in the instant specification are drawn to administration of empty particles such as empty liposomes; see at least page 88, paragraph 0314 of the instant specification. As such, it appears that in the instant application, applicant has discovered that administration of empty particles results in increased cell-free DNA in the blood. As such, the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. See MPEP 2112(I). In this case, a method of administering empty particles was taught by the prior art. Applicant discovered that this method results in increased cell-free DNA, which was unappreciated by the prior art, and may also be considered as a scientific explanation for what happens when the prior art method is carried out. However, this discovery does not render the claimed invention to be patentable, in view of the principles of MPEP 2112(I). Additionally, the inherent feature (e.g. that a method of administering empty particles inherently results in increased cell-free DNA concentration) need not have been recognized by the effective filing date. See MPEP 2112(II). See also MPEP 2112.02(I & II), 2114(II), 2144(IV), and 2145(II) drawn to latent properties present but not recognized by the prior art.
Additionally and/or in the alternative as to claim 1, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, on ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same See MPEP 2112(V). The burden of proof is similar to that required with respect to product-by-process claims. In this case, the examiner takes the position that the prior art is drawn to a method of administering an empty particle, which is the instantly claimed method. Additionally, that both Moghimi and the instant specification indicate that such a method is useful for affecting Kupffer cells. This is understood to be sufficient reasoning to shift the burden to applicant in accordance with MPEP 2112(V).
As to claim 1, the examiner notes that claim 1 requires that the nanoparticle comprises no therapeutically active material. The examiner takes the position that administration of an empty particle followed later by a particle with active agent is understood to meet this requirement. The requirement that the nanoparticle comprises no therapeutically active material does not exclude a case in which both a nanoparticle comprising no therapeutically active material and separately a nanoparticle comprising therapeutically active material are administered. See the section above entitled “Claim Interpretation.”
As to claim 2, the rationale under MPEP 2112 applied by the examiner to claim 1 also applies to claim 2.
As to claims 3-4, the prior art does not appear to teach the required quantities. Nevertheless, the skilled artisan would have been motivated to have optimized the number of nanoparticles and/or amount of nanoparticles per body weight. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). In this case, the general conditions of a method of administering empty nanoparticles is taught by the prior art. As such, it would not have been inventive for the skilled artisan to have determined the optimum or workable ranges of said empty nanoparticles via routine experimentation. The examiner notes here that the reason for which the empty nanoparticles are administered differs in the prior art as compared with the claimed invention; nevertheless, this difference is insufficient to overcome the applied rejection. 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 MPEP 2144(IV).
As to claim 5, Moghimi teaches intravenous administration as of page 31, abstract.
As to claim 7, the inherency argument made by the examiner with respect to claims 1 and 2 also applies to claim 7.
As to claim 8, the inherency argument made by the examiner with respect to claims 1 and 2 also applies to claim 8. However, the examiner further notes here that Moghimi provides significant teachings regarding the effect of empty particles on Kupffer cells, as of at least page 35, above-reproduced text, which would appear to bolster the examiner’s case for inherency.
As to claim 9, Germain teaches liposomes as of multiple locations in the reference, including but not limited to paragraphs 0094-0097.
As to claim 10, Germain teaches a liposome comprising dipalmitoyl phosphatidylcholine, which is abbreviated as DPPC, as of Germain, paragraph 0092, and is understood by the examiner to be a synthetic phosphatidylcholine.
As to claim 12, both Germain and Moghimi teach liposomes. The examiner understands liposomes to have an internal aqueous phase. As such, the examiner understands that liposomes encapsulate water, which is an inert material.
As to claim 13, this claim is rejected for essentially the same reason that claim 1 is rejected. See the rejection above under 35 U.S.C. 112(b).
As to claim 16, Germain teaches a particle size between about 30 nm and about 300 nm in paragraph 0027, which is within the claimed range.
As to claim 17, Moghimi teaches particles with half-lives in the 90 minute and 130 minute range, as of Moghimi, page 39, section IV(A).
As to claim 18, Germain teaches a -25 mV in paragraph 0089.
As to claim 19, Moghimi teaches intravenous administration as of page 31, abstract.
As to claims 20 and 22, Germain teaches cancer treatment as of at least paragraph 0011. Germain also teaches a human patient in paragraph 0065.
As to claim 23, Germain teaches breast cancer in paragraph 0013. The examiner notes that the nanoparticles discussed in this paragraph include clodronate; however, Germain teaches undesirable effects of clodronate in this paragraph, and also teaches empty particles in paragraph 0012. As such, the skilled artisan would have been motivated to have modified the decoy particles discussed in paragraph 0013 to have been empty and to have not included clodronate.
As to claim 95, Germain teaches nanoparticles containing gold in paragraph 0063.
As to claim 96, Germain teaches mannose modified liposomes in paragraph 0156; the skilled artisan would have understood this to have been a Kupffer cell targeting moiety, as of pages 25-26 of the office action mailed on 30 April 2026.
Examiner Note Regarding Potential Claim Amendment
The examiner notes that if applicant were to amend instant claim 1 to further recite a method step of extracting cell-free DNA, such an amendment would appear to overcome the above-applied rejection. This is because neither Germain nor Moghimi teach such a method step nor provide motivation for the skilled artisan to have conducted such a method step.
However, this proposed claim amendment would not clearly result in the claims being allowable because it would necessitate additional consideration under 35 U.S.C. 101 at least because cell-free DNA is a natural product. See at least MPEP 2106.04(b)(I)(x), citing Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015). Such a proposed amendment would be unlikely to be considered after-final because it would entail a new area of consideration under 35 U.S.C. 101.
Response to Arguments
Although the applied rejection is a newly applied rejection, the examiner takes the position that various arguments presented in applicant’s response on 29 July 2026 appear to be relevant regarding the applied rejection. As such, these arguments will be addressed below.
Applicant makes the following argument on the paragraph bridging pages 7-8 of applicant’s response, relevant text reproduced below.
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In response, the examiner notes that instant claim 22 further limits the patient population to be drawn to human patients who have, are suspected of having, or are at risk for a disease associated with the presence of cell-free DNA, which may include cancer. As best understood by the examiner, every human who does not already have cancer is at risk for having cancer. As such, the examiner best understands the patient population of “a subject in need thereof” to be drawn to all humans because all humans are at risk for having cancer.
The examiner additionally notes that Germain teaches administration to patients who have cancer, as of at least paragraph 0011.
As such, the examiner takes the position that the fact pattern of the cited case is insufficient to overcome the applied rejections.
Conclusion
No claim is allowed.
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 ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at (571)272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612
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