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 .
DETAILED ACTION
Summary
This is a Non-Final Office action based on the 18/763980 RCE filed on 04/17/2025.
Claims 1-23 are pending and have been fully considered.
Claims 22-23 are newly added.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/17/2025 has been entered.
Claim Objections
Claim 2 is objected to because of the following informalities:
With respect to Claim 2, “particle,” is used and it should be “particles.” Appropriate correction is required.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-23 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-60 of co-pending Application No. 18/547831 in view of FAROKHZAD in view of DAWSON as shown below.
18/547831 claims a method of selecting surfaces for a biomolecule assay, comprising: (a) providing one or more biological samples comprising a plurality of biomolecules; (b) contacting the one or more biological samples with a plurality of surfaces, such that each surface in the plurality of surfaces adsorbs a subset of biomolecules in the plurality of biomolecules; (c) determining, for each surface in the plurality of surfaces, abundances of the subset of biomolecules adsorbed thereon; and (d) selecting a subset of surfaces in the plurality of surfaces based at least in part on the abundances when the subset of surfaces adsorbs biomolecules or biomolecule groups that comprise a different abundance pattern compared to another subset of surfaces in the plurality of surfaces.
18/547831 does not teach that only 1% by mass of proteins are absorbed or that 1000 protein groups can be identified however FAROKHZAD in view of DAWSON teach this as shown below. It would have been obvious to one of ordinary skill in the art at the time of invention to detect lowly abundance proteins as is done in DAWSON and one would have had reasonable expectation of success to combine with FAROKHZAD due to the need in the art for better methods/systems for detection of complex protein mixtures (DAWSON, paragraph 0002).
Claims 1-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 & 28-30 of copending Application No. 18/174444 in view of FAROKHZAD in view of DAWSON as shown below.
18/174444 claims a method for analyzing a biological sample from a subject, comprising: (a) assaying said biological sample from said subject to identify proteins in said biological sample to obtain proteomic information of said biological sample, wherein said proteomic information comprises signals assignable to a first plurality of proteins or protein fragments of said proteins in said biological sample; (b) analyzing nucleic acid molecules from said biological sample to identify genotypic information of said biological sample, wherein said genotypic information comprises signals assignable to a second plurality of proteins or protein fragments associated with said nucleic acid molecules; and (c) based on said proteomic information and said genotypic information, identifying a peptide variant or a genomic variant of said subject, wherein said peptide variant or said genomic variant is not otherwise identifiable in (a) or (b), respectively, wherein said identifying comprises identifying said peptide variant or said genomic variant based at least in part on a signal of said genotypic information which overlaps with a signal of said proteomic information.
18/174444 does not teach that only 1% by mass of proteins are absorbed or that 1000 protein groups can be identified however FAROKHZAD in view of DAWSON teach this as shown below.
It would have been obvious to one of ordinary skill in the art at the time of invention to detect lowly abundance proteins as is done in DAWSON and one would have had reasonable expectation of success to combine with FAROKHZAD due to the need in the art for better methods/systems for detection of complex protein mixtures (DAWSON, paragraph 0002).
Claims 1-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 17/822110 in view of FAROKHZAD in view of DAWSON as shown below.
17/822110 claims a method for assaying a plurality of biomolecules, the method comprising: (a) labeling the plurality of biomolecules with distinguishable tags; (b) contacting the plurality of biomolecules with one or more surfaces to thereby adsorb the plurality of biomolecules on the one or more surfaces; and (c) assaying the plurality of biomolecules adsorbed on the one or more surfaces to identify at least a subset of the plurality of biomolecules based at least partially on the distinguishable tags.
17/822110 does not teach that only 1% by mass of proteins are absorbed or that 1000 protein groups can be identified however FAROKHZAD in view of DAWSON teach this as shown below.
It would have been obvious to one of ordinary skill in the art at the time of invention to detect lowly abundance proteins as is done in DAWSON and one would have had reasonable expectation of success to combine with FAROKHZAD due to the need in the art for better methods/systems for detection of complex protein mixtures (DAWSON, paragraph 0002).
Claims 1-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-28 of copending Application No. 17/099331 in view of FAROKHZAD in view of DAWSON as shown below.
17/099331 claims a method for assaying a biological sample, comprising: (a) contacting the biological sample with a plurality of particles comprising different particle types to permit biomolecules of the biological sample to bind to the plurality of particles and form coronas around the plurality of particles, wherein the coronas corresponding to the different of particle types (i) differ based on particle type, and (ii) comprise overlapping and distinct proteins; (b) separating at least a subset of the plurality of particles comprising the coronas from the biological sample by removing the subset of the plurality of particles thereby producing a subset of proteins from the biological sample; (c) assaying the subset of proteins of (b) with an instrument to detect, in the subset, proteins in the biological sample at concentrations across a broad dynamic range, thereby assaying the biological sample.
17/099331 does not teach that only 1% by mass of proteins are absorbed or that 1000 protein groups can be identified however FAROKHZAD in view of DAWSON teach this as shown below.
It would have been obvious to one of ordinary skill in the art at the time of invention to detect lowly abundance proteins as is done in DAWSON and one would have had reasonable expectation of success to combine with FAROKHZAD due to the need in the art for better methods/systems for detection of complex protein mixtures (DAWSON, paragraph 0002).
These are provisional nonstatutory double patenting rejections.
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 & 2-23 which depend from Claim 1 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 certain types/combinations of particles,” “sample,”s and isolating/digestion/mass spectrometry techniques--- which result in ensuring, “the total mass of absorbed proteins from the sample determined based on the assayed peptides is no more than about 1 % by mass of the proteins in the sample,” does not reasonably provide enablement for the realm of all possible “particles,” “sample,”s and isolating/digestion/mass spectrometry techniques--- which result in ensuring, “the total mass of absorbed proteins from the sample determined based on the assayed peptides is no more than about 1 % by mass of the proteins in the sample,” by these terms. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
With respect to the above, it seems that ways to control the, “total mass of adsorbed proteins,” being “no more than about 1% by mass of the total proteins in the sample,” is some combination of the generically claimed particles, what the specific sample is, and what reaction conditions are present for the claimed, “contacting,” “isolating,” “digesting,” and “assaying,” which are all claimed in little detail.
Generic particles would not control the “total mass of absorbed proteins,” to the claimed level of specificity instantly claimed which is, “the total mass of the adsorbed proteins from the sample determined based on the assayed peptides is no more than about 1% by mass of total proteins in the sample.” Also, all types of samples, do not all have the same amounts of proteins initially present in them.
This decision was made in taking into consideration all of the “Wands” factors (See MPEP 2164.01(a)) including:
(A) The breadth of the claims: The claimed “particles”, what the specific sample is, and what reaction conditions are present for the claimed, “contacting,” “isolating,” “digesting,” and “assaying” are claimed so broadly that all which all which can be interpreted in meeting these limitations would not result in the claimed, “total mass of adsorbed proteins,” being “no more than about 1% by mass of the total proteins in the sample.” The overall breadth of the claim is broad.
(B) The nature of the invention: The invention is directed to a method of assaying a sample using particles and a combination of contacting, isolating, digesting, and assaying by mass spectrometry.
(C) The state of the prior art: FAROKHZAD in US 20180172694 teaches of sensor arrays for detecting biomolecules and methods of use. FAROKHZAD teaches of obtaining samples from at least two subjects diagnosed with the disease or disorder and at least two control subjects; (b) contacting each sample with a sensor array to produce a plurality of biomolecule corona for each subject, and (c) comparing the composition of the plurality of biomolecule corona of the subjects with the disease or disorder to the composition of the plurality of biomolecule corona of the control subjects to determine a pattern of biomarkers associated with the disease or disorder (paragraph 0016), and further that the samples can be plasma (paragraph 0029).
FAROKHZAD teaches that the sample/plasma is contacted with a sensor array which can be a plurality of particles which bind/adsorb to the sample (paragraphs 0023-0024, 0071, 0144, 0310-0311). Further, it is taught that the biomolecules (e.g. proteins) bound to the particles can be isolated in a protein solution for further analysis, for example to determine the compositions of the proteins bound to each type of particle (e.g., anionic, neutral and cationic particles) (paragraph 0182), the digested (paragraph 0362, 0431), and then of characterizing the sample by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (paragraph 0183). FAROKHZAD further teaches of identifying 1000 different sets of samples to identify the protein corona system (reads on assaying “to identify at least 1000 proteins groups”) (paragraph 0368).
FAROKHZAD further teaches that complex biological samples have differing physiochemical properties and therefore a method of distinguishing the state of these samples requires particles with varying physiochemical properties as well (paragraphs 0022-0023).
(D) The level of one of ordinary skill: The level of ordinary skill in this art is high, as assaying through mass spectrometry and using digestion techniques requires knowledge of chemistry and the fact that proteins are analyzed requires knowledge of biochemistry. Even given that is the case, one would not be able to just guess which specific techniques and particles disclosed result in the claimed % amount of absorbed proteins in comparison to the initial sample.
(E) The level of predictability in the art: While assay techniques using particles and mass spectrometry was a developed field at the time of the invention and so had some measure of predictability, to assay as claimed to results of no more than 1% amount of proteins absorbed in comparison to the amount of proteins present in the initial sample, requires specific combinations of the claimed parameters. As claimed with respect to the broad “particles,” “sample,” “contacting,” “isolating,” “digesting,” and “assaying,” the result is unpredictable and would not result in the claimed “no more than about 1%.”
(F) & G The amount of direction provided by the inventor & The existence of working examples: The inventor does provide some amount of direction, but again does not provide enough direction to show how one would be able to arrive at the claimed result of “no more than about 1%.”
Example 1 describes how sample dilution affects particle corona (the amount of proteins or other molecules adsorbing to a particle) formation.
Example 2 described the effect of total particle surface area on the biomolecule corona formation.
Example 3 describes particle specific electrostatics and covers the interdependence between particle change and protein affinity.
Example 4 describes protein compression effects from protein corona occupancy.
Example 5 describes protein corona dependence on pH and particle surface.
Example 6 describes pH dependent particle adsorption by three serum proteins.
Example 7 describes the time dependence of protein corona formation.
Example 8 describes protein corona buffer-dependence.
Example 9 describes tailoring aggregate substrate surface area to maximize adsorbed protein diversity.
Example 10 describes the effect of diminishing particle concentration on biomolecule corona composition.
Example 11 describes a multi-concentration particle assay.
Example 12 describes a particle panel dilution assay.
Example 13 describes a multi-concentration particle assay with two particle panels.
Further, Figures 11 & 12 show adsorption isotherms for particles contacted by a range of samples with different protein concentrations. Panels A and B depict two distinct saturation behaviors. They graphically illustrates a series of protein-particle binding calculations, based on the equilibrium binding equation q.sub.e=((C.sub.0−C.sub.e)*V)/m, where q.sub.e is equilibrium adsorption (mass protein adsorbed per mass of particle), C.sub.0 is initial protein concentration, C.sub.e is equilibrium protein concentration, V is sample volume, and m is particle mass.
One would have to speculate from these parameters however as to what combination of parameters would result in the claimed “no more than about 1% by mass of total proteins in the sample,” being absorbed to the particles and quantified.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure: For the reasons shown above, which are in sum that the applicant does not provide guidance as to how to arrive at the claimed “no more than about 1% by mass of total proteins in the sample,” being absorbed to the particles and quantified, making and using the invention would require undue experimentation and so the scope of the invention is not enabled. More clarity and greater detail with regards to what parameters give the claimed results should have been provided.
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 1-23 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.
With respect to Claim 1, step (d) claims: “assaying said peptides to identify protein groups and quantitate a total mass of adsorbed proteins from the sample, wherein the assaying comprises mass spectrometry, at least 1000 protein groups are identified, and, when quantified, the total mass of adsorbed proteins from the sample determined based on the assayed peptides is no more than about 1% by mass of total proteins in the sample.”
This is unclear/confusing. In this quoted section of the claim—identification of “protein groups,” and “at least 1000 protein groups,” are claimed. It is then claimed that “the total mass of absorbed proteins from the sample based on the assayed peptides is no more than about 1% by mass of the total proteins in the sample.”
With respect to this, it is unclear what the relationship between a “protein group,” and just a “protein” which is absorbed is, and how one goes from adsorbing proteins at the beginning of the claim to identifying “protein groups,” since only “peptides,” are assayed for.
Also—the “total mass,” being “not more than about 1% by mass of the total proteins in the sample,” limitation is unclear as well since it is “based on the assayed peptides,” but the assayed peptides are used to identify “protein groups,” and not “proteins,” or “total proteins.” There is a disconnect between the “peptides,” “proteins,” and “protein groups,” as claimed.
Claims 2-23 are rejected by virtue of being dependent on Claim 1.
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.
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) 1-23 is/are rejected under 35 U.S.C. 103 as being obvious by FAROKHZAD in US 20180172694 in view of DAWSON in US 20120046184.
With respect to Claims 1 & 7-8, FAROKHZAD teaches of a method of using sensor arrays for detecting biomolecules and determining a disease state in a subject (abstract). More specifically FAROKHZAD teaches of obtaining samples from at least two subjects diagnosed with the disease or disorder and at least two control subjects; (b) contacting each sample with a sensor array to produce a plurality of biomolecule corona for each subject, and (c) comparing the composition of the plurality of biomolecule corona of the subjects with the disease or disorder to the composition of the plurality of biomolecule corona of the control subjects to determine a pattern of biomarkers associated with the disease or disorder (paragraph 0016), and further that the samples can be plasma (paragraph 0029).
FAROKHZAD teaches that the sample/plasma is contacted with a sensor array which can be a plurality of particles which bind/adsorb to the sample (paragraphs 0023-0024, 0071, 0144, 0310-0311). Further, it is taught that the biomolecules (e.g. proteins) bound to the particles can be isolated in a protein solution for further analysis, for example to determine the compositions of the proteins bound to each type of particle (e.g., anionic, neutral and cationic particles) (paragraph 0182), the digested (paragraph 0362, 0431), and then of characterizing the sample by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (paragraph 0183).
FAROKHZAD further teaches of identifying 1000 different sets of samples to identify the protein corona system (reads on assaying “to identify at least 1000 proteins groups”) (paragraph 0368). FAROKHZAD further teaches that the method includes analyzing for the presence of low abundance proteins, of which are only 1% of the proteome- which comprises over 10,000 proteins (paragraphs 0366-0367), and specifically of detecting low-abundance and rare proteins using multi-liposomes (paragraph 0075 & Figure 12 & paragraph 0347 & 0228). FAROKHZAD teaches that these low abundance proteins (which are detected by being adsorbed) are present at concentration of < 100 ng/ml and <10 ng/ml (paragraph 0367). This means that since the low abundance proteins are detected that “less than “about,” 1 % by mass,” of the proteins in the biofluid,” are adsorbed.
FAROKHZAD and having multiple different sensor elements with the nanoparticles with varying properties or different liposomes on them (paragraph 0228, 0226). FAROKHZAD teaches of detecting low-abundance and rare proteins even in the presence of the high abundance proteins (paragraph 00254), and further that the low abundance proteins & rare proteins, are only 1% of the proteome (this also includes the .1 % by mass proteins and .01% by mass proteins) (paragraph 0366-0367).
Therefore, FAROKZHAD is in fact teaching of detecting the 1% by mass of proteins as claimed, and specifically of detecting low-abundance and rare proteins using multi-liposomes (paragraph 0075 & Figure 12 & paragraph 0347 & 0228) and a sensor array which can be a plurality of particles which bind/adsorb to the sample (paragraphs 0023-0024, 0071, 0144, 0310-0311).
Further, since FAROKZHAD teaches of the claimed contacting, isolating, digesting, and assaying as broadly claimed—the claimed result of these steps of “no more than about 1 % by mass of total proteins in the sample,” would be the result.
FAROKZHAD just teaches of an additional step, in which the 99% of mass of proteins can also be detected. It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to detect/use nanoparticles that only adsorb the 1% by mass of proteins as instantly claimed--- using only one type of a plurality of nanoparticles as claimed to simplify the instant method.
Further, since all the claimed elements were known in the prior art as shown above, one skilled in the art could have combined or separated the elements as claimed by known methods with no change in their respective functions and this would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
However, if this is not apparent to one of ordinary skill in the art assay with respect to absorbing only low abundance protein’s (less than 1 % of proteins is a measure of abundance), DAWSON is used to remedy this.
DAWSON teaches of a method for isolation and removal of a cellular component by applying a pulse of nanoparticles (abstract, paragraph 0003), and further of harvesting and detecting very rare intracellular and low abundance cell components including rare signaling proteins (paragraph 0003, 0006). The cell component detected can be a protein that makes up less than .1% of the total protein in the serum concentration (paragraph 0012) (this also includes proteins that make up less than .01 %), and the nanoparticles selectively bind the low abundance or rare molecule (paragraph 0013). DAWSON teaches that these rare molecules are identified from a complex biological system which includes over 1000 different biomolecules (paragraph 0021) which can be proteins (paragraph 0012). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention and one would have at reasonable expectation of success to detect lowly abundance proteins as is done in DAWSON and one would have had reasonable expectation of success to combine with FAROKHZAD due to the need in the art for better methods/systems for detection of complex protein mixtures (DAWSON, paragraph 0002).
With respect to Claim 2, FAROKHZAD teaches that the sensor elements/particles can be microparticles (paragraph 0179).
With respect to Claim 3, FAROKHZAD teaches of the particles having different physicochemical properties (paragraphs 0076-0092, Claim 26) and further teach of analysis by desitometry (paragraph 0138 & 0144). The figure shows different densities for the different types of nanoparticles.
With respect to Claim 4, FAROKHZAD teaches of the sensor arrays containing nanoparticles (paragraph 0076, 0094-0121, 0241-0243).
With respect to Claim 5, FAROKHZAD teaches that the sensory elements/sensory array elements/nanoparticles containing elements that differ from eachother in at least one physiocochemical property (paragraph 0009, 0200, 0076, 0094-0121, 0241-0243).
With respect to Claim 6, FAROKHZAD teaches that physiocochemical property of the sensor element found in an array refer to, for example, the composition, size, surface charge, hydrophobicity, hydrophilicity, surface functionality (surface functional groups), surface topography, surface curvature and shape. The term composition encompasses the use of different types of materials and differences in the chemical and/or physical properties of materials, for example, conductivity of the material chosen between the sensor elements (paragraph 0201-0204).
With respect to Claim 9, FAROKHZAD teaches of the nanoparticles being magnetic nanoparticles (having magnetic cores) (paragraph 0215, 0382).
With respect to Claim 10, See Claim 1, & 7-8 rejection. FAROKHZAD further teaches that samples can be plasma (paragraph 0029).
With respect to Claim 11, FAROKHZAD teaches that the sensor elements/particles can be microparticles (paragraph 0179). FAROKHZAD further teaches of the particles can be magnetic nanoparticles (having magnetic cores) (paragraph 0215, 0382)(magnetic nanoparticles are also considered magnetic nanoparticles since they are micron sized or smaller).
With respect to Claim 12, FAROKHZAD teaches of the particles being polyethylene imine particles (paragraph 0217).
With respect to Claim 13, FAROKHZAD teaches of combining the sample with PBS buffer (paragraph 0415).
With respect to Claim 14, FAROKHZAD teaches of the claimed invention as shown above. FAROKHZAD does not teach of modifying the fluid to pH of 5. DAWSON is used to remedy this and teaches of the claimed invention as shown above. DAWSON further teaches of the pH of the nanoparticles being pH of 5 (paragraph 0165). DAWSON teaches that the nanoparticles are mixed with the sample (paragraph 0102-0103). Since the two are mixed, this reads on modifying the biofluid to pH of “about 5.” It would have been obvious to one of ordinary skill in the art to modify the biofluid pH due to the advantage this offers for activating specific moieties/functional groups (paragraph 0165).
With respect to Claim 15, FAROKHZAD teaches of identifying concentrations of proteins in the biofluid in the pg/ml range of 1-10pg/ml (less than 500 pg/ml) (paragraph 0173, 0367).
With respect to Claim 16, FAROKHZAD teaches of detecting at 1-10pg/ml for cytokine proteins which reads on the claimed “less than 1 microgram.ml) (paragraph 0173).
With respect to Claim 17, FAROKHZAD teaches of sensor array has a sensitivity and dynamic range of ten (10) orders of magnitude in terms of protein detection using mass-spectroscopy approaches (which reads on the instantly claimed “at least 9”). The present assay is able to detect proteins that are found in the sub-ng range within a sample. This assay or approach has a much greater dynamic range than current assays for measuring proteins within a sample. For example, mass spectrometry only has a dynamic range 4-6 order of magnitude. This novel sensor array has the ability to sample a greater dynamic range than has previously been achievable. The present sensor array allows for detection and determination of low abundant and rare proteins that we not previously able to be detected (paragraph 0176).
With respect to Claim 18, FAROKHZAD teaches of sensor array has a sensitivity and dynamic range of ten (10) orders of magnitude in terms of protein detection using mass-spectroscopy approaches (which reads on the instantly claimed “at least 10”). The present assay is able to detect proteins that are found in the sub-ng range within a sample. This assay or approach has a much greater dynamic range than current assays for measuring proteins within a sample. For example, mass spectrometry only has a dynamic range 4-6 order of magnitude. This novel sensor array has the ability to sample a greater dynamic range than has previously been achievable. The present sensor array allows for detection and determination of low abundant and rare proteins that we not previously able to be detected (paragraph 0176).
With respect to Claim 19, FAROKHZAD teaches of incubating the sample with the sensor array for about 20 minutes (paragraphs 0297-0298).
With respect to Claim 20, FAROKHZAD teaches of using plasma fractionating with the nanoparticles (paragraph 0367, 0366). DAWSON also teaches of fractionating the sample (paragraph 0066, 0073).
With respect to Claim 21, FAROKHZAD teaches of characterizing and identifying the proteins using LC-MS/MS (paragraph 0183, 0310, 0326, 0347, 0367, 0387, 0407, 0410, 0431).
With respect to Claims 22-23, FAROKHZAD teaches that the sample/plasma is contacted with a sensor array which can be a plurality of particles which bind/adsorb to the sample (paragraphs 0023-0024, 0029, 0071, 0144, 0310-0311).
Response to Arguments
Applicant's arguments filed 04/17/2025 have been fully considered but they are not persuasive.
Applicant’s make no substantive arguments about the double patenting rejection. Therefore the double patenting rejection is maintained as shown in the above rejection.
With respect to the prior art, applicant argues that neither of the reference disclose the claim limitation “wherein no more than about 1% by mass of the proteins in the biofluid are adsorbed to the plurality of particles,” and that 1000 protein groups are identified. The examiner disagrees. DAWSON teaches that these rare molecules are identified from a complex biological system which includes over 1000 different biomolecules (paragraph 0021) which can be proteins (paragraph 0012). The examiner disagrees, as the prior art does in fact in the very least make this claim limitation obvious.
FAROKZHAD teaches of detecting the 1% by mass of proteins as claimed, and specifically of detecting low-abundance and rare proteins using multi-liposomes (paragraph 0075 & Figure 12 & paragraph 0347 & 0228) and a sensor array which can be a plurality of particles which bind/adsorb to the sample (paragraphs 0023-0024, 0071, 0144, 0310-0311). The sensor array detection and which proteins are detected between high abundance and low abundance proteins in FAROKZHAD is dependent on how the sensor array is functionalized/what particles are used. When the multi-liposomes are used, the low-abundance and rare proteins are detected (paragraph 0075). FAROKZHAD teaches that low abundance proteins are 1% or less of the total proteome analyzed (paragraphs 0366-0367), which means that when the low abundance particles/multi-liposomes are used for detection, “no more than about 1 % by mass of the proteins in the biofluid are adsorbed,” as instantly claimed.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that the instant invention is able to detect at the level claimed (1000 protein groups and with the assayed peptides being no more than 1% of the total protein in the sample), is a discovery by applicant and that this is due to improved instrumental detection. Applicant further argues that applicant has found that “adsorbing less overall mass of proteins can in fact increase the diversity of proteins that are detected.” Applicant argues that their claimed results are unexpected.
With respect to all of these things, the examiner notes that an enablement rejection was made as shown above since the full scope of the instant claims is not enabled by the specification and specifically it is not enabled for result in the claimed result of no more than 1% of the total protein in the sample being adsorbed and allowing for the detection of the claimed amount of protein groups. Applicant should narrow the claims to what enables the claimed results.
Applicant further argues that the cited reference fail to suggest an advantage/ unexpected results achieved by the instantly claimed invention that is “methods which utilize low particle concentrations to enhance adsorbed biomolecule diversity.” This is not convincing. With respect to this—the examiner points out that if this is in fact true and an advantage, applicant has not claimed how exactly only absorbing a small mass of proteins improves this diversity. How does applicant ensure that only that small mass is absorbed? Is the signal for detection improved or clearer some way because of this? It is assumed the small mass is enabled to be absorbed, by the particular particles used for adsorption. As this is the case- the prior art makes the instant claims obvious, especially as broadly claimed.
All claims remain rejected.
Conclusion
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758