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 .
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 1-4, 6-11, 19-20, and 22-25 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.
Regarding claims 1 and 19 the claims recite “a fluorophore … modified with biorthogonal conjugates”; however, it is unclear how or if the structure of the conjugates or the nanoparticle as a whole are modified by being “biorthogonal”. That is, there is no meaningful way to interpret the conjugates as being “a pair of topological vector spaces that are in duality with a pair of indexed subsets” and as such no clear meaning to the claim limitation at issue. For compact prosecution purposes the examiner notes that the limitation “azide, azido, alkyne, tetrazine, alkene, and combinations thereof” would be clear on its and the examiner recommends removing the term “biorthogonal”. To further compact prosecution the examiner notes that instead claiming that the conjugates are “bioorthogonal” would require a rejection under 101 and section 33 of the AIA for positively reciting that the human body acts on the structures at issue and therefore the examiner does not recommend this as it does not narrow the scope of the structures used in the modification and it would raise a further grounds of rejection for the claims. Claims 1-4, 6-11, 20, and 22-25 are each similarly affected at least by virtue of dependency.
Claim Rejections - 35 USC § 103
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 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) 1-4, 7-9, 19, 21-22, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over WO2014187800A1 by Fredriksson et al. (hereafter Fredriksson) further in view of [hereafter IVO] US 20180223260 A1 by Aprikyan et al. (hereafter Aprikyan), these references being taken together or alternatively as evidenced by [hereafter AEB] US 20190345534 A1 by Kwong et al. (hereafter Kwong).
Regarding claim 1, Fredriksson teaches: 1. A nanoparticle (see Fredriksson’s Claim 1 noting that the invention is generally a nanoparticle of 5-100 nm size) comprising:
a magnetic core comprising a magnetic nanocrystal (see Fredriksson’s Claims 1+8 wherein claim 1 establishes that the size of the core and claim 8 establishes the composition. Alternatively see Fredriksson’s Summary of Invention on page 11 lines 28-32 or further alternatively see Fredriksson’s page 15 line 4 to page 16 line 4; each of which covers the fundament of the core structure among many other sections); and
a coating covering greater than or equal to about 80% of a total surface area of the magnetic core (the ordinary meaning of coating in a dissolved/aqueous solution is ~100% as such that the very second sentence of Fredriksson’s Abstract, which states in relevant part “The agent is produced by coating cores” covers this limitation. However and to be even more clear the Abstract continues by stating “whereby the core is coated and a poly-chelator network is formed around the core during the coating process to form the final product which is a nanoparticle with the polymer (compound II) as the outer component of the formed nanoparticle” such that it is clear that the outer component (i.e. not just some of the outside) includes the polymer), the coating comprising:
a polymer … (the use of a polymer including functional groups with both amine (i.e. amino terminal polymer, - compound II) and maleimide (poly maleic anhydride) and carboxyl (side structure of carboxylic groups) is covered in Fredriksson’s very Abstract; with other polymers covered in further sections (e.g. dextran on pages 21-22)), and
one or more detectable agents associated with a functional group of the polymer, the one or more detectable agents comprising:
a fluorophore (see Fredriksson’s page 22 lines 20-33 which explains the use of a fluorophore, specifically the fluorescent dye “DY-647 (Dyomics)” and also how this is bonded to the Super-Paramagnetic Iron Oxide Nanoparticle (hereafter SPION) core which is an agent detectable fluorescently), the fluorophore being a modified base fluorophore that is sulfated, isothiocyanated, modified with an N-hydroxysuccinimide ester, modified with a maleimide, modified with biorthogonal conjugates selected from the group consisting of: azide, azido, alkyne, tetrazine, alkene, and combinations thereof, or any combination thereof (given that the claim does not specify any particular type or requirement as to what constitutes “modified” and given that the foregoing addresses bonding this to the polymer coating, the examiner notes that merely containing or being bonded to such a group either directly or indirectly would read on such broad drafting. To that end, many of these options are explicitly taught by Fredriksson. For example, the examiner notes that any of the SMPH bonding already addressed below or NHS bonding that has previously been addressed above (e.g. Fredriksson’s page 22 lines 20-33) would necessarily read on this, likewise the reaction of poly maleic anhydride (e.g. Fredriksson’s Abstract) already addressed above would seemingly also read on this, likewise the use of fluorophores that already had such groups would read on this so e.g. Fredriksson’s use of cadmium sulfide quantum dots would read on this (e.g. Fredriksson’s page 17 lines 1-13), likewise the use of DY-647 already bonded to such groups would also address this as, further referenced below and with additional references already of record, as Dy-647 is configured to be provided as an NHS-ester, amino-derivative, maleimide, or carboxylic acid bonded form per se for easy attachment which would each read on these groupings. However and for compact prosecution purposes the examiner notes that Fredriksson’s general statements of “Amino groups in the coating are used to conjugate the dye through N-Hydroxysuccinimide (NHS) chemistry” circa Fredriksson’s page 22 lines 20-33 is a singular and succinct rejection of one of the iterated options which would apply to any of his fluorophore choices and to the modifications of the fluorophores below as it has to do with the bonding (i.e. modifying) of the fluorophore and which uses the same sort of modification the applicant appears (i.e. based on their specification) to address instead of relying on the breadth of the claim language);
at least one chelating compound coupled to the magnetic core, the at least one chelating compound being a compound that chelates copper-64 (64Cu), a compound that chelates technetium-99m (99mTc), or a combination thereof; and an iodine chelator (regarding both of these together, it can be seen in Fredriksson’s very abstract that his invention is intended to be a “poly-chelator”; however, see also the Summary of Invention which states that the object of the invention is to chelate metal ions and radionuclides as per page 11 line 27 to page 12 line 4 states “This innovation describes a coating material with the inherent capability to chelate metal ions and radionuclides in the interior of the coating” and to further and more clearly differentiate between mere multi-site chelators and true poly-chelators see also page 14 lines 5-21 wherein Fredriksson clearly spells out that “the resulting nanostructure is perfect as combined contrast agent for MRI/PET (or SPECT) or optical imaging/PET (or SPECT) or CT/PET (or SPECT) or ultrasound/PET (or SPECT) or CT/PET (or SPECT) if the metal that is chelated is a radionuclide or multiple various radionuclides.”; from there it only remains to be established that Fredriksson acknowledges that Iodine, Cu64, and Tc99 are radionucleotides and Fredriksson also does not disappoint on this issue was he indicates that Iodine is a radionucleotide useful for fluoroscopy and RIT as per page 3 lines 22-30 and page 5 line 30 to page 6 line 2 respectively. Likewise Fredriksson also notes that both Cu64 and Tc99 are radionucleotides useful for PET/SPECT as per page 3 lines 22-30 and/or page 19 lines 10-23. Lastly, the fact that these are all bonded to the core should be clear, but the step of bonding the chelators to the core is covered on page 11 line 27 to page 15 line 2 wherein many different coating polymers are described which serve to link the core to the various modality specific chelators as described. Lastly and just to thoroughly flesh out the details the examiner also notes that chelators of this sort are well known in the art, and that this fact is recognized by Fredriksson in the foregoing citation. Likewise this same citation also iterates that the process of making this contrast agent is such that “the resulting nanostructure is perfect as combined contrast agent for MRI/PET (or SPECT) or optical imaging/PET (or SPECT) or CT/PET (or SPECT) or ultrasound/PET (or SPECT) or CT/PET (or SPECT)” and to clarify that this is also for more than the combined listing of modalities including all of these modalities as per page 7 lines 14 to 24 which are agents detectable under the above cited modalities), and …
In the foregoing the examiner omitted, as indicated by ellipsis, the limitations “succinimidyl 6-((beta-maleimidopropionamido)hexanoate) (SMPH) coupling the iodine chelator to the magnetic core” and that the polymer is such that it is “comprising poly ethyl methacrylate, poly methyl methacrylate, or a combination thereof” because while Fredriksson uses iodine chelators he does not describe their coupling in detail and because while Fredriksson uses a polymer coating on the core he uses polymers other than PEMA or PMMA so as to fail to teach these two new limitations.
However; regarding both of these and regarding the latter of these in detail, the examiner notes that Aprikyan in the same or nearly identical field of bonding functional groups to polymer coated magnetic nanoparticle cores (see [0028] and [0035] which teach this succinctly, though one could also simply see it pictorially from viewing Figs. 1, such that Aprikyan differs from Fredriksson only on choosing different functional groups to enact treatment instead of enhance imaging but must solve the same bonding problem in order to do so) teaches that PMMA is a useful polymer for coating magnetic nanoparticles (see Aprikyan’s [0217]-[0221] which describe both that PMMA can be used in a polymeric coating, notably with other polymers in a combined coating or in a similar fashion to many other polymers utilized by the applicant’s specification and some dependent claims including dextran, PEG, lysine, etc. among numerous other polymers utilized by the applicant’s specification). Aprikyan also goes on to teach that such a polymer coating is advantageous (in these same sections, namely [0217]-[0221] Aprikyan also states that the surface coating improves the stability of the nanoparticle including the temperature stability and resistance to degradation in vivo and affects (i.e. allows for choosing) the solubility and targeting of the nanoparticle, insofar as different polymers are more or less biocompatible, more or less soluble, etc. advantageously allowing for one to pick a polymer or set of polymers more or less suitable for particular applications). Notably Aprikyan also happens to teach that SMPH is a well-known cross linker for this use case (e.g. as per [0277] “Crosslinking agents known in the art as … SMPH … may also be used to prepare the functionalized nanoparticles disclosed herein.”) so address all issues with Fredriksson, though for compact prosecution purposes the examiner notes that a secondary evidentiary reference has been added below as it allows for an even stronger rejection to be made as well as the fact that the examiner has added yet another reference to the conclusion section teaching advantages to using SMPH in this exact same context.
Therefore, it would have been obvious to one of ordinary skill in the art prior to the date of invention to improve the nanoparticle of Fredriksson with the use of the PMMA in the polymer coating and, at least alternatively, to use SMPH as the linking agent taught by Aprikyan because it advantageously would allow for using a coating that can be functionalized and which that had improved stability as well as to allow one to vary the solubility and targeting potential of the nanoparticle.
Furthermore and alternatively and regarding the former deficiency of Fredriksson in more detail, the examiner notes that Kwong, teaches that SMPH (and for that matter SPDP, the majority of the specific species of linking agents of the applicant’s original disclosure) are both well known in the art (i.e. see MPRP 2144.03) and also to be suitable for bonding functional groups to polymer coated magnetic nanoparticle cores (i.e. see MPEP 2144.06) as described by Kwong (see Kwong’s [0088] which describes linkers known to be suitable for joining the functional groups (e.g. peptide sequences among others) to the scaffolds (i.e. nanoparticles) which includes SMPH per se and many others. For the sake of clarity, the examiner notes that the scaffold being a nanoparticle is both the base embodiment (e.g. see Kwong’s Figs. 1-2A) and can be a magnetic nanoparticle of the sort used by Fredriksson per se (e.g. see Kwong’s [0013]) and the functional group can also include a reporter which can be specifically a contrast agent for one or more of PET, CT, MRI, fluorescence, etc. as per Kwong’s [0147] all of which is useful for understanding just how accurately the statement of suitability would apply; though in any event the mere showing that these are useful for linking things to a magnetic nanoparticle core would be more than enough to clarify that Kwong’s statement of suitability would clearly apply to linking things to the nanoparticle of Fredriksson. Likewise this same section of Kwong at [0088], in addition to calling these linkers suitable, explicitly calls them “well known to those of skill in the art”).
Therefore and in the alternative, it would have additionally or alternatively been prima facie obvious to one of ordinary skill in the art prior to the date of invention to use any of the various linking agents such as SMPH for linking the iodine chelator to the magnetic core of Fredriksson either because these linking agents including SMPH are old and well known and/or because these linking agents including SMPH are art recognized to be suitable for linking things to magnetic cores.
Regarding claim 2, Fredriksson teaches: 2. The nanoparticle according to claim 1, wherein the magnetic nanocrystal comprises iron oxide and the magnetic core has a diameter of greater than or equal to about 1 nm to less than or equal to about 50 nm (Fredriksson teaches this in many sections and teaches various ranges such as 1-10 nm, 1-50, 2-50 etc. To give a single clear example, see Fredriksson’s Abstract which uses a core size of 2-50 nm).
Regarding claim 3, Fredriksson teaches: 3. The nanoparticle according to claim 1, wherein the magnetic core is a first magnetic core, the magnetic nanocrystal is a first magnetic nanocrystal, and the nanoparticle further comprises: one or more second magnetic cores, wherein each of the one or more second magnetic cores comprising a second magnetic nanocrystal (as best understood in light of the applicant’s specification this is actually “one or more cores” which is taught as given above in regards to claim 1; however, Fredriksson teaches what the applicant appears to regard as resulting in multi-core nanoparticles in at least two ways. First, Fredriksson teaches that one can use multiple growth steps to achieve the preferred size of nanoparticle also appears to support that there would be multiple separate nanocrystals first perspective, see e.g. page 15 line 25 to page 16 line 4 resulting in nanostructures (plural) which is in line with one of few differences between the applicant disclosed differences between the single core versus multi-core formation discussed below in the response to arguments. Secondly the examiner notes that the term core is not limited to a single structure therefore even if (arguendo) all of the Fe3O4 nanocrystals formed by Fredriksson were monocrystalline per se the fact that these are 1) smaller crystals of e.g. 15, 34, or 57 nm in size; 2) subject to a polymerization process, and then 3) filtered with a 200 nm filter (see Fredriksson’s Example 2, from page 21 line 5 to page 23 line 5) means that Fredriksson’s protocol can create and retain contrast agent particles which have, as a core, multiple small SPION crystals and that many of these nanoparticles exist in the media per se).
Regarding claim 4, Fredriksson further teaches that the coating further comprises dextran (regarding these together, see Fredriksson’s page 11 lines 28-32 teaching coating the magnetic cores in a polymer in view of page 13 lines 7-22 coving the use of dextrans to form this layer and lastly page 14 lines 3-21 showing how the chelators are linked therewith – as previously cited); however, Fredriksson does not give the molecular weight of the dextran he employs and therefore fails to fully teach: “having an average molecular weight of greater than or equal to 1,000 g/mol to less than or equal to 100,000 g/mol”.
However, the examiner notes that while Fredriksson does not directly disclose the size of the dextran he uses, it must necessarily be much less than 300kD as the filtration steps used by Fredriksson limit the size of the entire nanoparticle using a 300kD filter (see Fredriksson’s page 22 first paragraph noting the filtration steps). As such it is fundamentally clear that while Fredriksson does not explicitly teach this limitation that he does teach a range that overlaps therewith (e.g. given that the dextran is not necessarily the only polymer and that the core and other components reasonably take up the a substantial amount of this kD disparity one could reasonably assert that the dextran must be <= 150 kD, but even the range of <300 kD still strongly overlaps with the claimed range of 1-100 kD) and therefore Fredriksson teaches a range that overlaps with the claimed range.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the date of invention to use dextrans of 1-100 kD as the dextrans of undisclosed but overlapping size provided by Fredriksson as per MPEP 2144.05(I).
Regarding claims 7-9 Fredriksson teaches the basic invention as given above in regards to claim 1 but does not contain the same exact terminology about the chelators and therefore fails to explicitly teach: “7. The nanoparticle according to claim 1, comprising the compound that chelates 64Cu, the compound that chelates 64Cu being S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DOTA-NHS-ester), 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), or combinations thereof. 8. The nanoparticle according to claim 1, comprising the compound that chelates 99mTc, the compound that chelates 99mTc being [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (SCN-Bn-CHx-DTPA). 9. The nanoparticle according to claim 1, wherein the iodine chelator is thyroxine (T4), triiodothyronine (T3), or a combination thereof.”
However, the claim limitations appear to be prima facie obvious in at least two ways as follows:
First, these chelators are old and well known in the art. Not only is this the examiner’s opinion, but it is expressly endorsed by Fredriksson who teaches that metal chelators for these same ions are old and well known in the art per se (see Fredriksson’s page 13 lines 4-6 which state: “Metal chelates are well known in the art. Some well known are known as DOTA, DIPA, TETA NOTA. The above are only examples, also other macrocyclic metal chelates may be used.”) and it also appears to be not only a legally appropriate argument given the contents of the applicant’s specification, e.g. lack of any disclosed criticality associated with any of the these particular claimed chelators, but also appears to be the applicant’s express position as well given that the applicant has not made any remarks as to how to synthesize, where to get, why to use, advantages of, etc. for any of the claimed chelators and has gone so far as to not even define (in the specification or claims) the acronyms used to describe these chelators (e.g. “DOTA” is never defined) clarifying that it must also be the applicant’s position that these structures, their uses, and the reasons to use them, etc. are so well known that they do not bear mention as exemplified by the applicant’s specification at [0074] wherein the applicant recites “In some example embodiments, well-known processes, well-known device structures, and well-known technologies are not described in detail.” Such that, given the lack of even the most basic of statements about these structures it must be the case that these are acknowledged by the applicant as being well known as otherwise they would lack so much information as to necessitate a 112(a) rejection for lacking adequate written description. Given the prior arts’ similar treatment of chelators as exceedingly well-known and general use of these elements with little description it appears that these elements are in fact something properly addressed by the applicant as so well known and no 112(a) rejection has been raised, though the use of acronyms without defining them is still objectionable even if they are well known. However and to that end, it appears that there is a strong prima facie case that all of these chelators are in fact widely regarded as well known in the art and therefore that the claim should be rejected under the legal precedent set forth by MPEP 2144.03 as one of ordinary skill in the art would have been appraised that these chelators were well known options available for use.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the date of invention to employ the claimed chelating compounds as the generic chelating compounds of Fredriksson as these compounds were old and well known in the art, at least in light of the legal precedent set forth in MPEP 2144.03.
Secondly and alternatively, the examiner notes that what is disclosed by Fredriksson appears to be in all instances analogs and in some instances to have clear and a close structural similarity to the claimed chelating compounds, making them prima facie obvious variants under MPEP 2144.09. To give a clear example where structural similarity is readily apparent, while the claims recite compounds such as “DOTA-NHS-ester” Fredriksson explicitly uses DOTA (see Fredriksson’s page 13 lines 4-6) which is the actual chelator whereas the NHS-ester is a peripheral for bonding that chelator. As such the prior art expressly teaches using the exact same functional group which differs only in that Fredriksson uses a variety of possible bonding elements (to give a limited example see Fredriksson’s claims 2-4), none of which are explicitly and exactly “NHS-ester” but where there is a resounding and concrete case that the DOTA will have the same properties of chelating the same ions whether or not certain components are used to bond it to the cores and likewise it would be seemingly impossible to argue that DOTA would not have, at the very least, similar properties to DOTA which is the actual standard set forth in MPEP 2144.09. Likewise this same line of reasoning appears to obviate each choice for each claimed chelating compound even if the structural teachings are not as clear given that, As established above in regard to claim 1, Fredriksson sets forth that he chelate the exact same set of ions as the claims and therefore his chelators are at the very least functional analogs (i.e. see MPEP 2144.09(III), this applies – as the title of the section states clearly - to analogs and does not require a specific structural relationship, e.g. see the cited case law wherein different ring structures and even amino-acid substitution (despite being the core functional component) have been held to be prima facie obvious under this title, such that the substitution of one chelator for another, so long as they are purposed for the same end and known to serve the same function, is indicated to be obvious) of the claimed chelating compounds in all instances and certainly does so in exactly the same way and level of detail as would be required to hold this obvious over every statement made about these chelators in the applicant’s specification (i.e. see MPEP 2144.09(VII), noting that the applicant’s specification does not so much as mention the utility or compare/contrast various rational for using or not using a particular chelator and indeed has no disclosed purpose or utility to the compounds other than merely to chelate the ions and makes effectively no other statement about the chelating compounds in question that would in any way call into doubt whether or not other chelators for the same ion would be regarded by the applicant as being in any important way different from the claimed chelating compounds thus nothing of record rebuts or provides any indication that there would be unexpected, or even mildly different, results obtained by using similar or analogous chelators. Indeed, to continue the previous examples we can readily discern that the applicant specification simply does not mention whether or not NHS-esters make any difference one way or another or refer to other DOTAs. Furthermore, in the sole instance found by the examiner of a statement which mentions alternative chelators the applicant appears to expressly iterate that other chelators can be used to perform the function, see [0089] of the applicant’s specification which states “As non-limiting examples, the iodine chelator 22 can be T4, T3, or a combination thereof. Conventional iodine tracers can also be used as the iodine chelator 22.” Where no other statements, for-or-against, using alternative chelators exists for any other claimed chelating compound clarifying an express lack of criticality for the specific choice of chelator and also demonstrating a clear overlap in scope and function between the other chelators known in the art and those which are included by name).
Therefore and in the alternative, it would have been prima facie obvious to one of ordinary skill in the art prior to the date of invention to treat the prior art chelators and claimed chelating compounds as obvious variants given the structural similarity and/or analogous relationships between these compounds, at least in light of the legal precedent set forth in MPEP 2144.09.
Regarding claim 19, Fredriksson teaches: 19. A method of imaging at least one of a tissue or a metabolic process in a subject (see Fredriksson’s Abstract), the method comprising:
administering to the subject a composition comprising a contrast agent, (as best understood is inherent in administration of a contrast agent of the sort addressed below and thus taught, e.g. by showing that it is for internal use in a patient during imaging which can be covered by Fredriksson’s very Abstract. To compact prosecution the examiner also notes that it may be useful to see Fredriksson’s Page 9 line 32 to page 10 line 7 noting that “To be useful as contrast agents in such applications the nanoparticles has to be: designed to give contrast in the chosen imaging modality (ies) - biocompatible with a surface that minimize unspecific interactions - capable of being functionalized in order to directed the nanostructure to specific target sites in the body following systemic administration [i.e. be administrable]), the contrast agent comprising:
[the verbatim text of the body of claim 1 and examiner’s rejection thereof are not repeated herein for the sake of brevity; see the foregoing rejection of claim 1 which is incorporated herein by reference to show how the contrast agent composition is taught by Fredriksson IVO Aprikyan, alternatively AEB Kwong]
performing at least one of magnetic resonance imaging (MRI), magnetic particle imaging (MPI), fluorescence (FL) imaging, photoacoustic (PA) imaging, ultrasound (US) imaging, positron emission tomography (PET), single-photon emission computed tomography (SPECT), X-ray imaging, or computed tomography (CT); and generating an image of the tissue or the metabolic process with contrast provided by the contrast agent (regarding these two steps together, see e.g. Fredriksson’s page 7 lines 14-24 for performing multiple of these imaging modalities and where each such image will at least be an image of the tissue or metabolic process as that is best understood).
Regarding claim 22, Fredriksson teaches: 22. The method according to claim 19, comprising: performing at least two of the MRI, the MPI, the FL imaging, the PA imaging, the US imaging, the PET, the SPECT, the X-ray imaging, or the CT; and generating at least two images of the tissue or the metabolic process, each of the at least two images comprising contrast provided by the contrast agent (again regarding these two steps together, see e.g. Fredriksson’s page 7 lines 14-24 for performing multiple of these imaging modalities and where each such image will at least be an image of the tissue or metabolic process as that is best understood).
Regarding claim 24, Fredriksson teaches: The nanoparticle according to claim 1, wherein the coating further comprises polyethylene glycol (PEG) (the examiner notes that Fredriksson’s claim 3 already covers this as it uses functionalized PEG, where the use of PEG is also disclosed on Fredriksson’s pages 13-14 in constructing polymer compounds I-II).
Claim(s) 20 is rejected under 35 U.S.C. 103 as being unpatentable over Fredriksson further IVO Aprikyan alternatively AEB Kwong as applied to claim 19 above, and further in view of Injection (medicine) by Wikipedia.
Regarding claim 20, while Fredriksson teaches the basic invention as given above in regards to claim 19, and even teaches that the preparations can be formatted for injection (see e.g. Fredriksson’s page 21 lines 29-31) including that the contrast agent comprises a pharmaceutically acceptable carrier (water and saline are both acceptable carriers, therefore see Fredriksson’s page 26 line 24 to page 27 line 9 teaches this as it states e.g.: “After removal of the chloroform the volume of water solution containing the particles was measured and an equal volume of 300 mM NaCl was added, to make the SPIONs solution ready for injection.” And even noting that the same section states that the result is that the final product is a standard saline solution (i.e. 0.9% salt / 0.15 M NaCl) when ready to be used in imaging) and used in applications which are e.g. specifically intraductal and/or intratumoral (see page 4 line 11 to page 5 line 29 and page 5 line 30 to page 6 line 19) however, Fredriksson never actually states that the injection should be intravenously, intraductally, intrathecally, or intramuscularly, intratumorally per se and therefore fails to explicitly teach: “20. The method according to claim 19, wherein the administering is performed intravenously, intraductally, intrathecally, intramuscularly, intratumorally, or orally;”
However, one cannot merely “inject” something they have to instead inject it in some fashion (e.g. intravenously inject). Therefore Fredriksson teaches a genus and the claims instead require one or more species thereof. To that end and in accordance with both MPEP 2131.02(III) and/or 2144.08 it is clear, IVO Injection (medicine) that multiple claimed species of injection are prima facie obvious, and even at once envisaged from the broader generic term “injection”. Specifically, Injection (medicine) teaches that injections are among the most common health care procedures and that the most common forms of injection includes at least intramuscular and intravenous. Therefore, the examiner is of the opinion that one of ordinary skill in the art, being a medical professional, could at once envisage that intramuscular or intravenous injections could be performed for an injection of unknown form and dually iterates that this sort of species would, as evidenced by Injection (medicine) be at least prima facie obvious from the generic term “injection”.
Therefore it would have been at once envisaged, or otherwise it would have been prima facie obvious to one of ordinary skill in the art prior to the date of invention to utilize specific forms of injection such as intravenous or intramuscular injection as the generic injection taught by Fredriksson.
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fredriksson IVO Aprikyan alternatively AEB Kwong as applied to claim 1 above, and further in view of DY-647 – DISCONTINUED by Dyomics (hereafter Dyomics).
Regarding claim 6 while Fredriksson teaches the basic invention as given above in regards to claim 1 including that he uses a fluorophore such as “DY-647 (Dyomics)” as cited above, Fredriksson does not explicitly elaborate as to the composition of the fluorescent dye he uses nor is information on how the dye is made readily available given that the dye is discontinued by its manufacturer and therefore Fredriksson alone fails to fully teach: “6. The nanoparticle according to claim 1, wherein the fluorophore is selected from the group consisting of a cyanine dye, a coumarin, a rhodamine, a xanthene, a quantum dot, derivatives thereof, and combinations thereof.”
However Dyomics, in the same identical field of fluorophores – as it is the manufacturer of DY-647 cited in the primary reference, teaches explicitly that Cy5 (a Cyanine dye) is suitable for the same purpose as it contains the comment “Spectral similar to Cy5 and Alex Fluor 647” (see Dyomics page 1, comments section). As such it would be art recognized as a suitable replacement for the discontinued dye of the primary reference. See also MPEP 2144.07.
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the date of invention to replace the discontinued fluorophore taught by Fredriksson with cyanine based fluorophore listed by the original fluorophore’s manufacturer Dyomics as a suitable replacement, at least in light of the legal precedent set forth under MPEP 2144.07.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fredriksson IVO Aprikyan alternatively AEB Kwong as applied to claim 1 above, and further in view of Ultrasmall Mixed Ferrite Colloids as Multidimensional Magnetic Resonance Imaging, Cell Labeling, and Cell Sorting Agents by Groman et al. (hereafter Groman).
Regarding claim 10, Fredriksson teaches the basic invention as given above in regards to claim 1 including that the claimed elements should be bound to the core, but Fredriksson does not teach that the linker should be epichlorohydrin and therefore fails to teach: “10. The nanoparticle according to claim 1, wherein the fluorophore, the compound that chelates 64Cu, the compound that chelates 99mTc, or the combination thereof and the iodine chelator are coupled to the magnetic core by a linker, the linker being aminated epichlorohydrin.”
However, Groman in the same or eminently related field of multimodal imaging using iron oxide nanoparticle cores bonded to additional modality contrasts (see Groman’s abstract) teaches that one can use epichlorohydrin as a linker to bond the additional contrasts to the core (see the Cross-Linking and Amination of USMIO Colloids section on page 1764 or the Chemical Properties section on pages 1767-1768 both of which cover using epichlorohydrin to bond to the core, aminiating it, and then further reacting the aminated epichlorohydrin to link various molecules thereto including specifically at least plural types of fluorophores) and that it is advantageous to do so (see the Discussion section on 1769-1771 noting that in discussing the chemical properties of a particle so constructed the particle is held to have stability against environmental challenge).
Therefore it would have been obvious to one of ordinary skill in the art prior to the date of invention to improve the invention of Fredriksson with the use of aminated epichlorohydrin in order to advantageously allow for highly stable bonding of the contrast particles.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fredriksson IVO Aprikyan alternatively AEB Kwong as applied to claim 8 above, and further alternatively IVO Multifunctional magnetic nanoparticles for targeted imaging and therapy by McCarthy et al. (hereafter McCarthy).
Regarding claim 11, Fredriksson IVO Aprikyan alternatively AEB Kwong obviates the base invention as given above in regards to claim 8 and also teaches that SPDP is a well-known and suitable linking agent for use on magnetic cores as per the amended rejection to claim 1 above; however, for compact prosecution purposes it can be noted in the alternative that:
However McCarthy in the related field of iron oxide nanoparticle based medicine (see McCarthy’s abstract) teaches that one can use SPDP is an appropriate cross-linking agent for iron oxide nanoparticles which allows bonding between the nanoparticle core and peripherals such as antibodies or peptides (see section 2 Chemistry of surface modification on pages 1242-1243 where SPDP is specifically discussed and its use in bonding the core to other useful surface modifications including various peptides and antibodies), where McCarthy goes on to teach that SPDP in particular is a useful cross-linker (as per McCarthy’s Section 2 on pages 1242-1243 SPDP has particular advantages insofar as: “One of the main advantages of utilizing SPDP is that it can be used to determine the number of reactive amines on the particle, as pyridine-2-thione is released upon reaction with dithiothreitol (DTT), can be detected spectrophotometrically, and thus quantitated. Reaction of ligands with SPDP functionalized particles also liberates pyridine-2-thione, thus allowing the number of conjugated species to be determined.”).
Therefore it would have been obvious to one of ordinary skill in the art prior to the date of invention to improve the invention of Fredriksson with the use of SPDP as a cross-linker between his core and chelator because it advantageously allows for monitoring the state of the nanoparticle surface and the progress and amount of conjugation.
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fredriksson IVO Aprikyan alternatively AEB Kwong as applied to claim 1 above, and further in view of Quantum Dots in Bioanalysis: A Review of Applications across Various Platforms for Fluorescence Spectroscopy and Imaging by Petryayeva et al. (hereafter Petryayeva).
Regarding claim 23 and further/alternatively regarding claim 6, Fredriksson teaches the basic invention as given above in regards to claim 1, but Fredriksson uses a different fluorophore than the claim and therefore fails to teach: “The nanoparticle according to claim 1, wherein the fluorophore is selected from the group consisting of a coumarin, a rhodamine, a xanthene, a quantum dot, derivatives thereof, and combinations thereof”.
However Petryayeva in the same or related field of fluorescent imaging teaches that quantum dots can function as a fluorophore with the same utility/spectra as DY-647 used by Fredriksson or any other spectra that the current need may require (see the Optical Properties of Quantum Dots section and note that quantum dots spectral profiles can be tailored based on their size, something that is in and of itself both advantageous and makes this technology prima facie suitable for replacing the defunct/discontinued dye used by the primary reference) furthermore, Petryayeva goes on to provide additional advantages to even further motivate the modification (as per the Optical Properties of Quantum Dots section “Other advantageous optical properties of QDs include excited state lifetimes that tend to be longer than those of fluorescent dyes (>10 ns), superior resistance to photobleaching and chemical degradation”).
Therefore it would have been obvious to one of ordinary skill in the art prior to the date of invention to improve the invention of Fredriksson with the use of quantum dots as the fluorophore as taught by Petryayeva in order to advantageously take advantage of the ability to have tailor made spectral profiles, longer fluorescent lifetimes, and superior resistance to photobleaching among other advantages thereof.
Claim(s) 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fredriksson IVO Aprikyan alternatively AEB Kwong as applied to claim 1 above, and further in view of US 20100055042 A1 by Yathindranath et al. (hereafter Yathindranath).
Regarding claim 25, Fredriksson IVO Aprikyan alternatively AEB Kwong as applied to claim 1 above teaches the basic invention; however, while Fredriksson uses various polymer coatings and Apyrikyan shows that the related substance PMMA is an appropriate coating choice, neither reference uses PEMA and thus fail to fully teach: “wherein the polymer comprises poly ethyl methacrylate.”
However Yathindranath in the same or eminently related field of polymer coated imageable magnetic iron oxide nanoparticles capable of receiving surface modifications (see Yathindranath’s Abstract and [0046] for this being iron oxide nanoparticles that are polymer coated and for this being useful in imaging in addition to the other coating uses respectively so as to at least be in a related field and so as to solve a relevant problem of biocompatible and modified coatings for magnetic nanoparticles) teaches that a variety of polymers are suitable in terms of both biocompatibility and ability to receive further modification including at least PEMA, PMMA, PEG, among others and the advantages to using these polymers (see any of Yathindranath’s Abstract, [0004], [0010]/[0033], [0026], or [0039] among others which spell out that each of these polymers, including PEMA per se, can be bonded to magnetic nanoparticle cores and also that this is advantageous for various reasons including its biocompatibility, ability to remain well dispersed in water, having the potential to act as a drug carrier etc. Notably this leads to two potential modifications, one where the advantages of PEMA themselves motivate the combination or one where [0010/0033] simply spell out that this is explicitly recognized by the art to be suitable for the same application as Fredriksson and Aprikyan used polymers like PEG or PMMA respectively).
Therefore, it would have been obvious to one of ordinary skill in the art prior to the date of invention to substitute other polymer coatings such as PEMA for the polymer/PMMA used by the base references because PEMA in particular is advantageously demonstrated to have both comparable biocompatibility and also the ability to stay well suspended and/or because the art explicitly recognizes that these polymers are each all suitable for the same application per se, see MPEP 2144.07.
Response to Arguments
Applicant's arguments filed 09/17/2025 with respect to the 103(a) rejection of the claims under Fredriksson IVO Aprikyan alternatively as evidenced by Kwong have been fully considered but they are not persuasive.
Specifically, the applicant’s argument on pages 12-15 for all previously pending claims is that neither the base references nor any of the modifying references teach the newly recited claim language and in particular the modification to the fluorophore. In this instance the examiner remarks that Fredriksson alone rather clearly teaches this limitation in previously cited section which addressed the fluorophore and how it was bonded to the polymer and which specifically used NHS chemistry per se, e.g. see Fredriksson’s Page 22 lines 20-33 or see the Non-Final Office Action at page 4. To that end the examiner disagrees with the applicant’s position and is not convinced that the claims define over the prior art. Additionally the examiner notes that multiple of the modifying references also appear to teach this subject matter but that these are not further argued at this point because Fredriksson already provides such teachings. Lastly, the exceedingly broad drafting (e.g. having any azide, azifo, alkyne, tetrazine, alkene, etc. group would be a basic rundown of the most common groups used in click chemistry and they do not have to be employed in any specific modification) has also caused the examiner to include multiple references in the conclusion section that the applicant may find informative and which could form the basis of a future rejection if the applicant chooses to narrow how to base fluorophore is intended to be modified.
On page 15 the applicant separately regards the new claim. In this instance the examiner notes that the previous references did not use PEMA and thus the examiner has provided a new ground of rejection that cites new art and that the rejection of claim 25 can be incorporated herein to show why the examiner is not convinced by the argument that this new claim is patentable.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure is as follows:
Carboxyfluorescein succinimidyl ester by Wikipedia is a back dated reference which the examiner happened to already be aware of and which can be used to show an old and well-known dye labeling technique that could be applied to read on the newest claim limitations set forth by the applicants and therefore serves as a backup for the currently applied prior art.
Bioorthogonal chemistry by Wikipedia is a back dated reference which the examiner considered when determining whether to issue a 112(a) rejection of the new claim language given that the applicant did not specify a single pathway or reaction that they were using nor what tissue or enzyme they were targeting. In this instance the examiner notes that bioorthognal chemistry in specific (and click chemistry more generally, which overlaps significantly with what is claimed) are both quite old and well known and this single back dated article give examples of all of the applicant’s claimed conjugates such that the examiner notes that any and all individual conjugates in the applicants claims and specification are well known in the art under MPEP 2144.03.
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/MICHAEL S KELLOGG/Examiner, Art Unit 3798
/PASCAL M BUI PHO/Supervisory Patent Examiner, Art Unit 3798