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 .
Claims 1-11 are pending and under examination on the merits.
Applicant’s election without traverse of the species of:
1. for the degradable spacer (P)-an acetal;
2. for the Y moiety-an antibody; and
3. for the precursor- a sulfonate
in the reply filed on 05/19/2026 is acknowledged.
Priority
Applicant’s claim of priority to EP22196631.0, filed 09/20/2022, is acknowledged. The priority documents have been electronically retrieved.
IDS
The information disclosure statement (IDS) filed 05/17/2024 has been considered.
Specification
The disclosure is objected to because of the following informalities:
“Object” at paragraph 0007 at page 2 of the specification should read “An object”;
“G. Lerche et al, Bioorg Chem 20 (2021) 571-582)” at paragraph 0010 should read “G. Leriche et al, Bioorg Chem 20 (2012) 571-582)”;
“intracellular or extracellular” at paragraph 0015 at page 3 of the specification should read “intracellularly or extracellularly”;
“Suitable precursors comprises” at paragraph 0029 should read “Suitable precursors comprise”; and
“Preferable” at paragraph 0034 should read “Preferably”.
Appropriate correction is required.
Claim Interpretation
Samples are being interpreted to refer to a sample from a single biological source/origin, not a composite.
Claim Objections
Claim 5 is objected to because of the following informalities: “nucleic acids segments” should read “a nucleic acid segment”.
Claim 9 is objected to because of the following informalities: “+-0,5” should read “+/- 0.5”.
Claim 11 is objected to because of the following informalities: “+-0,5” should read “+/- 0.5”.
Appropriate correction is required.
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) 1-7 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yagnik et al (J Am Soc Mass Spectrom. 2021 Apr 7;32(4):977-988. doi: 10.1021/jasms.0c00473. Epub 2021 Feb 25; citation 13 under Non-Patent Literature on the 05/17/2024 IDS) in view of Lee et al (Org Biomol Chem. 2015 Aug 21;13(31):8445-52. doi: 10.1039/c5ob01056j), Rady et al (Bioconjug Chem. 2022 Oct 19;33(10):1860-1866. doi: 10.1021/acs.bioconjchem.2c00314. Epub 2022 Sep 15), and Andraos et al (Chemistry of Materials 1998 10 (6), 1694-1699, DOI: 10.1021/cm980052b).
Regarding claim 1, Yagnik et al teach the formula 1 of claim 1 (see their figure 1 at page 978) and teach Immunohistochemistry (IHC) combined with fluorescence microscopy provides an important and widely used tool for researchers and pathologists to image multiple biomarkers in tissue specimens. However, multiplex IHC using standard fluorescence microscopy is generally limited to 3–5 different biomarkers, with hyperspectral or multispectral methods limited to 8. Yagnik et al report the development of a technology based on photocleavable mass-tags (PC-MTs) for facile antibody labeling, which enables highly multiplexed IHC based on MALDI mass spectrometric imaging (MALDI-IHC). This approach significantly exceeds the multiplexity of both fluorescence- and previous cleavable mass-tag-based methods. Up to 12-plex MALDI-IHC was demonstrated on mouse brain, human tonsil, and breast cancer tissues specimens, reflecting the known molecular composition, anatomy, and pathology of the targeted biomarkers. Novel dual-labeled fluorescent PC-MT antibodies and label-free small-molecule mass spectrometric imaging greatly extend the capability of this new approach. MALDI-IHC shows promise for use in the fields of tissue pathology, tissue diagnostics, therapeutics, and precision medicine (see for example, the abstract at page 977).
Yagnik et al do not teach an acetal linker.
Lee et al teach that biotin is often used to capture the targeted protein due to its strong binding affinity for the egg-white glycoprotein avidin or to the bacterial protein streptavidin. However, conventional methods to release biotinylated proteins from streptavidin bead matrices are harsh because of the strong binding interaction. Recently, several biotin probes containing cleavable linkers have been developed to avoid such harsh elution conditions. Lee et al exploited the cyclic acetal moiety as an acid-sensitive linker. Orthoesters, ketals, and acetals are accepted cleavable linkers for drug delivery in vivo. In consideration of long term storage needs in combination with the requirements for stability in physiological conditions and fast cleavage for target identification, Lee et al designed cyclic acetals as acid-cleavable linkers (see for example, pages 8445-8446 and Figure 1). They are readily prepared by simple chemistry from commercially available starting materials. Lee et al introduce the synthesis and capture utility of cyclic acetal linkers in two model systems.
Lee et al do not teach the use of acid-labile (acid-cleavable) linkers to an antibody moiety (Ym).
However, Rady et al teach that cleavable linkers have become the subject of intense study in the field of chemical biology, particularly because of their applications in the construction of antibody-drug conjugates (ADC), where they facilitate lysosomal cleavage and liberation of drugs from their carrier protein. Due to lysosomes’ acidic nature, acid-labile motifs have attracted much attention, leading to the development of hydrazone and carbonate linkers among several other entities. Continuing their efforts in designing new moieties, Rady et al present a family of cyclic acetals that exhibit excellent plasma stability and acid lability, notably in lysosomes. Incorporated in ADC, they led to potent constructs with picomolar potency in vitro and similar in vivo efficacy as the commercially available ADC Kadcyla in mouse xenograft models (see for example, the abstract at page 1860). Cleavable linkers can be defined as chemical groups that can be cleaved in a controlled manner to release at least two distinct molecular entities. The resulting diversity of linker structures has been broadly classified into three main domains, depending on the conditions employed for their cleavage: enzymatic, physicochemical (i.e., photoirradiation), or chemical, the latter being undoubtedly the most populated and diversified group. Linkers sensitive to acidity/basicity, oxidation/reduction, or to nucleophilic species have been thoroughly explored and led to motifs that are now part of the general synthetic chemist toolbox. Interestingly, a second wave of interest in “chemically labile” structures has then emerged with the development of chemical biology in the last two decades, where cleavable linkers are used to connect a payload or a probe to a biomolecule interacting with biological targets. However, the stringent operating conditions imposed by biological environments (e.g., narrow temperature range, aqueous medium, low concentrations, presence of a myriad of biomolecules) have dictated the development of new types of linkers that can be cleaved under milder conditions, typically those found in various intracellular compartments. Indeed, one of the main applications of cleavable linkers in chemical biology resides in the intracellular delivery of compounds of interest, for example, for imaging or therapeutic purposes, which has necessitated the development of chemical moieties with excellent extracellular stability, to avoid premature release and potential off-target delivery of the payload, but rapid and efficient intracellular cleavage. New types of acid-sensitive linkers have been developed for this purpose, to take advantage of the marked differences between the acidity of certain organelles or tissues (e.g., lysosomes or tumor environments, with pH < 5.0), and that of physiological body fluids, with pH ∼ 7.0 on average. However, most of these acid-cleavable linkers also show partial instability in plasma, with half-lives ranging from a few minutes to 2–3 days, leading to risks of early drug cleavage and thus systemic toxicity in vivo. Rady et al, with this issue in mind, synthesized FRET probes, in which a TAMRA fluorophore was linked to a BHQ-2 quencher via known acid-sensitive moieties such as cyclic orthoester motifs or linear acetals (see for example Figure 1 at page 1861). Incubating these probes in different media, Rady et al saw that some were highly stable in human plasma but readily hydrolyzed under acidic conditions, as determined by monitoring the fluorescence intensity of TAMRA. Rady et al became interested in combining motifs from the second and third generation linkers to see the influence of methoxyphenyl groups on the stability of cyclic acetals, in the hope of developing a fourth generation of acetal-based linkers with an improved stability/cleavage balance (see for example, page 1861). Synthesis of FRET probes 5 and 6 incorporating a five-membered (m = 0) and a six-membered (m = 1) ring acetal, respectively (top panel of figure 2). Stability study of FRET probes 5 and 6 at different pH and in human plasma and the measured fluorescence is a direct indication of acetal hydrolysis and, by extension, of linker cleavage (bottom panel of figure 2) (see for example, page 1862). Acetals 5 and 6 were found to be readily hydrolyzed at pH ≤ 4.0 while being stable at neutral pH and in human plasma (see for example, page 1861). To validate that the vesicle-like distribution of TAMRA fluorescence was due to a cleavage in acidic organelles, subsequent incubation of SKBR-3 cells with 2 μM of LysoSensor Green DND-189 was also conducted. To our delight, red and green fluorescence signals seemed to be colocalized as indicated by an orange-yellow fluorescence signal in merged pictures, reinforcing our hypothesis of a lysosomal cleavage. While both probes 5 and 6 led to higher fluorescence values than ValCit probe 7 by flow cytometry analysis, even after only 30 min of incubation, it was interesting to notice that 6 gave systematically a 10-fold increase in fluorescence intensity compared with its five-membered ring homologue 5, a behavior that had not been seen during our stability studies in buffers (Figure 3). On the contrary, linear acetal probe 8 led to barely detectable fluorescence, confirming the microscopy results and its intracellular stability (see for example, page 1862).
The forgoing is deemed to read upon steps (a)-(c) of claim 1.
Yagnik et al, Lee et al, and Rady et al do not teach the use of a sulfonate precursor, but do teach and motivate the use of an acid to cleave the acetal linker, as noted above.
However, Andraos et al teach that the mechanism of photodissociation (using photoirradiation) and acid generation for three phenolic sulfonate esters, ranging from alkyl, to benzyl, to aromatic, was investigated by laser flash photolysis and product studies. All the sulfonate esters studied showed the presence of phenoxyl and other complex radicals in the transient spectra. The formation of these complex transients indicates that the radical pair formed upon excitation of the sulfonate can escape the solvent cage, and undergo further chemical transformations. It was observed that all of the sulfonate esters investigated resulted in the formation of acidic species. Photoproduct studies indicate that phenyl methanesulfonate and phenyl toluene-p-sulfonate undergo a photo-Fries type rearrangement and also produce a large excess of phenol with the corresponding sulfonic acid. Upon excitation, phenyl toluene-R-sulfonate undergoes near quantitative SO2 extrusion, with the formation of no Fries rearrangement photoproducts; instead it was observed that the benzyl radicals, generated by SO2 loss, undergo a “pseudo” Fries rearrangement to form the ortho and para phenylmethane isomers. Further, the SO2 photogenerated undergoes oxidative and hydrolytic processes to form sulfuric and sulfurous acids (see for example, the abstract at page 1694 and column 2 of page 1695).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because Yagnik et al teach photocleavable mass-tags (PC-MTs) for facile antibody labeling, which enables highly multiplexed IHC based on MALDI mass spectrometric imaging (MALDI-IHC) in the arrangement of instant formula I. Rady et al teach that cleavable linkers have become the subject of intense study in the field of chemical biology, particularly because of their applications in the construction of antibody-drug conjugates (ADC), with linkers that are cleavable with acid and/or photoirradiation being known genera in the art. Thus, it would have been obvious to use a cleavable linker such as that taught by Rady et al as the linker in the conjugate of Yagnik et al, the linkers serving the functionally equivalent function of linking the antibody to the detection/detectable moiety. Lee et al teach that acetal linkers are acid-cleavable (acid-labile), making them functionally equivalent linkers for use in the method according to reference A, Yagnik et al, and Rady et al and therefore obvious to use in said conjugate. This makes obvious and motivates the artisan to practice steps a-c of claim 1 with an antibody Y moiety and an acetal P linker of instant formula I. The artisan would have been motivated to use a known means in the art for generating an acid to cleave the acid-labile acetal linker of Lee et al. The artisan would have found the means of Andraos et al to be an obvious methos for acid-generation to try. Andraos et al teach that photoirradiation of a sulfonate (three sulfonates are examiner and shown to degrade to an acid subunit) generates an acid subunit, said acid subunit would have been obvious to use with the conjugate resulting from Yagnik et al, Lee et al, and Rady et al as the acid to cleave the acid-labile acetal linker between the antibody (Y moiety) and the detectable moiety (X). This motivates and makes obvious the practice of steps d-f of claim 1. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 2, as discussed above, sulfonates, such as the thee sulfonates tested by Andraos et al are cleaved by photoirradiation, presumably into at least 2 subunits (constituent parts), at least one of which being an acid.
Regarding claim 3, as discussed above, the acetal linker (P) is acid-cleavable such that the artisan would expect the acid generated by photoirradiation of the sulfonate to cleave the acetal linker, thereby cleaving the antibody (Y) from the detection moiety (X) by severing their connection to one another. Note also that Rady et al teach cleavage of the detection tag/moiety from the antibody in biomarker/IHC analysis, as discussed above.
Regarding claim 4, Yagnik et al teach the use of photocleavable mass tags (PC-MTs) which comprise an amine-terminal Fmoc-protected version of the photocleavable linker (PC-Linker; red) incorporated during conventional Fmoc-based solid-phase peptide synthesis (SPPS) along with the other amino acids. The example PC-MT shown is oriented with the N-terminal on the left and the C-terminal on the right. “APRLRFYSL” is an example amino acid sequence of the peptide mass unit (see Supplementary Table S1 for all mass units used in this work). The PC-MTs contain a spacer that connects the 1-(2-nitrophenyl)-ethyl-based photocleavable nucleus (PC-Nucleus) to the probe-reactive moiety (see for example, pages 978-979). Yagnik et al also teach that a fluorescent moiety may be used for detection (see for example, column 2 of page 979, pages 981-984, and page 986). Any and each of the mass tags of Yagnik et al or Yagnik et al’s fluorescent moiety is deemed to be, at least, a functional equivalent (see MPEP §§2143(I)(B) and 2144.06(II)) of the detection moieties recited.
Regarding claim 5, as discussed above, the combined references make obvious the use of an acetal linker (a degradable (interpreted as cleavable given that lack of a closed, preclusive definition of ‘degradable’ in the instant specification)) which is acid-labile/acid-cleavable (this is interpreted to read upon the recitation of the acidic cleavable functional units selected from the group consisting of acetals in the absence of a closed, preclusive definition/description in the instant specification).
Regarding claim 6, as discussed above, the combined references motivate and make obvious a conjugate of instant formula I wherein the Y moiety is an antibody.
Regarding claim 7, as discussed above, the combined references motivate and make obvious the use of a sulfonate precursor to be photoirradiated (photocleaved) into an acid subunit for cleaving the acetal linker. This is interpreted to read upon the recitation of the precursor comprising functional units selected from the group consisting of sulfonates in the absence of a closed, preclusive definition/description in the instant specification.
Regarding claim 9, given that the precursor generates an acid, there is a presumed change in the first pH (prior to photoirradiation) and the second pH (after photoirradiation). It is noted that the change in the pH (between a first and second pH) is not an active step, but it instead a result passively achieved by practicing the active steps of claim 1. Therefore, claim 9 is obvious for the same reasons as claim 1 because the result of claim 9 flows naturally from practicing the method of claim 1, as presently drafted.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yagnik et al, Lee et al, Rady et al, and Andraos et al , as applied to claims 1-7 and 9 above, in further view of Zabadal et al (The Journal of Physical Chemistry A 2001 105 (45), 10329-10333 DOI: 10.1021/jp010220e).
Regarding claim 8, as discussed above, Yagnik et al, Lee et al, Rady et al, and Andraos et al teach and make obvious instant claim 1. Rady et al further teach that linkers sensitive to acidity/basicity, oxidation/reduction, or to nucleophilic species have been thoroughly explored and led to motifs that are now part of the general synthetic chemist toolbox. Rady et al further explain that a second wave of interest in “chemically labile” structures has then emerged with the development of chemical biology in the last two decades, where cleavable linkers are used to connect a payload or a probe to a biomolecule interacting with biological targets. Andraos et al teach that the three sulfonates broke down to form an acid subunit when irradiated at 266nm (see for example, page 1696).
The combined references do not teach a second precursor which is activated at a different wavelength.
However, Zabadal et al teach that irradiation (direct photolysis) of DMP esters at 254−366 nm led to the formation of the free acids in high yields (see for example, the abstract at page 10329 and column 1 of page 10329).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because the MPEP provides that:
“[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In reKerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In reCrockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine)”,
(see MPEP §2144.06). Here, the 2 precursors (one of the sulfonates from Andraos et al and a DMP ester from Zabadal et al) activate at two different, non-overlapping wavelengths (the DMP ester activating at 254nm and the sulfonates of Andraos et al activating at 266nm). Both precursors produce an acid and are prima facie obvious to combine for use in the method as claimed because they are taught in the art to be useful for the same purpose of generating an acid upon photoirradiation. The sulfonates of Andraos et al are encompassed by the disclosed/recited genera of precursors and the DMP ester of Zabadal is at the least a functionally equivalent (see MPEP §§2143(I)(B) and 2144.06(II); where both function to produce an acid upon photoirradiation) photoacid generating precursor (noting that the only description of precursors beyond the mere naming of the genera disclosed is as a compound which is photocleaved/photolysed to provide an acid or base subunit for cleaving the linker (p) in instant formula 1). The wavelength that activates (photocleaves a precursor into an acid or base subunit) is an inherent property which the Office is not in a position to test. It is presumed that the recited genera of precursors would activate at different wavelengths. The MPEP provides that “[a]s a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972) (see MPEP §2113.III). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yagnik et al , Lee et al, Rady et al, and Andraos et al , as applied to claims 1-7 and 9 above, in further view of Aichler et al (Lab Invest 95, 422–431 (2015). https://doi.org/10.1038/labinvest.2014.156) and Park (pub. 2021 (as evidenced by ResearchGate); Far UV-C Radiation: Current State-of Knowledge, Downloaded from: https://www.researchgate.net/figure/Penetration-of-UV-wavelengths-into-human-skin-arrows-represent-an-estimate-of-90_fig4_351736833).
Regarding claim 10, as discussed above, the combined references make obvious the method of claim 1 and Yagnik teaches the conjugate for MALDI-IHC imaging.
Aichler et al teaches that Matrix-Assisted Laser Desorption Ionization (MALDI) has led the way in the development of biological and clinical applications for imaging mass spectrometry and is therein one of the most commonly used techniques. MALDI imaging has already entered disciplines beside medicine, microbiology as a standard technology for classification or plant pathology for investigating spatially resolved molecular information. This technology provides a broad range of features, which should be recognized by medicine- or pathology-related investigations. The great advantage of MALDI imaging is the correlation of molecular information with traditional histology by keeping the spatial localization information of the analytes after mass spectrometric measurement (see for example, page 422; presumably this is accomplished by localized application of the laser to the specimen).
Park teaches that photoradiation at wavelengths 200-400nm have a limited penetration, not going beyond the epidermis or dermis, depending on the selected wavelength (see Figure 11 for example at page 17).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to allow for advantageous correlation of molecular information with traditional histology by keeping the spatial localization information as taught by Aichler et al (such as by localized application of the radiation, limiting availability of acid/base from photocleaved precursor). It would have been obvious to the artisan to apply the conjugate and the precursor to the surface of the sample because light of 200-400nm had limited penetration (so surface application provides the best likelihood of success for the light to cleave the precursor resulting in acid which must be in proximity with the conjugate to cleave the acetal linker (P)). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 11, the only addition over the method of claim 10 is that there is a first pH (prior to activation of the precursor by application of radiation) and a second pH (after activation of the precursor by application of radiation) the first and second pH differing from one another by at least +/= 0.05. Given that the precursor generates an acid, there is a presumed change in the first pH (prior to photoirradiation) and the second pH (after photoirradiation). It is noted that the change in the pH (between a first and second pH) is not an active step, but it instead a result passively achieved by practicing the active steps of claim 10. Therefore, claim 11 is obvious for the same reasons as claim 10 because the result of claim 11 flows naturally from practicing the method of claim 10, as presently drafted.
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.
Claim(s) 1-7 and 9 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of reference A (US 10197561 B2) in view of Yagnik et al (J Am Soc Mass Spectrom. 2021 Apr 7;32(4):977-988. doi: 10.1021/jasms.0c00473. Epub 2021 Feb 25; citation 13 under Non-Patent Literature on the 05/17/2024 IDS), Lee et al (Org Biomol Chem. 2015 Aug 21;13(31):8445-52. doi: 10.1039/c5ob01056j), Rady et al (Bioconjug Chem. 2022 Oct 19;33(10):1860-1866. doi: 10.1021/acs.bioconjchem.2c00314. Epub 2022 Sep 15), and Andraos et al (Chemistry of Materials 1998 10 (6), 1694-1699, DOI: 10.1021/cm980052b).
Regarding claim 1, reference A claims a method for detecting a target moiety in a sample of biological specimens by:
a) providing at least one conjugate with the general formula (I) Xn —P—Ym, wherein X is a detection moiety, P is an enzymatically degradable spacer, Y is an antigen recognizing moiety and n, m are integers between 1 and 100 and wherein X and Y are covalently bound to P;
b) contacting the sample of the biological specimens with the at least one conjugate, thereby labelling the target moiety recognized by the antigen recognizing moiety Y;
c) detecting the target moiety labelled with the conjugate; and
d) enzymatically degrading the spacer P, thereby cleaving the detection moiety X from the conjugate,
wherein the detection moiety X is a fluorescent moiety, the enzymatically degradable spacer P is dextran, and the antigen recognizing moiety Y is Fab, and
wherein by enzymatically degrading the spacer P, the antigen recognizing moiety Y is also cleaved from the target moiety (see for example, claim 1 of reference A). The specification of reference A defines the Y moiety as preferably an antibody (see for example, column 8 of reference A). The specification of reference A defines the X moiety as any moiety possessing a property or function which can be used for detection purposes like those selected from the group consisting of chromophore moiety, fluorescent moiety, phosphorescent moiety, luminescent moiety, light absorbing moiety, radioactive moiety, and transition metal isotope mass tag moiety (see for example, column 5 of reference A).
Reference A does not clearly teach or claim radiation as part of imaging a biological specimen.
However, Yagnik et al teach the formula 1 of instant claim 1 (see their figure 1 at page 978) and teach Immunohistochemistry (IHC) combined with fluorescence microscopy provides an important and widely used tool for researchers and pathologists to image multiple biomarkers in tissue specimens. However, multiplex IHC using standard fluorescence microscopy is generally limited to 3–5 different biomarkers, with hyperspectral or multispectral methods limited to 8. Yagnik et al report the development of a technology based on photocleavable mass-tags (PC-MTs) for facile antibody labeling, which enables highly multiplexed IHC based on MALDI mass spectrometric imaging (MALDI-IHC). This approach significantly exceeds the multiplexity of both fluorescence- and previous cleavable mass-tag-based methods. Up to 12-plex MALDI-IHC was demonstrated on mouse brain, human tonsil, and breast cancer tissues specimens, reflecting the known molecular composition, anatomy, and pathology of the targeted biomarkers. Novel dual-labeled fluorescent PC-MT antibodies and label-free small-molecule mass spectrometric imaging greatly extend the capability of this new approach. MALDI-IHC shows promise for use in the fields of tissue pathology, tissue diagnostics, therapeutics, and precision medicine (see for example, the abstract at page 977). Yagnik et al teach that MALDI imaging involves the use of a spatially defined laser to apply radiation to achieve photocleavage (see for example pages 979-980).
Reference A and Yagnik et al do not teach or claim that the linker is acid/base labile by an acid/base subunit resulting from irradiating a precursor.
However, Lee et al teach that biotin is often used to capture the targeted protein due to its strong binding affinity for the egg-white glycoprotein avidin or to the bacterial protein streptavidin. However, conventional methods to release biotinylated proteins from streptavidin bead matrices are harsh because of the strong binding interaction. Recently, several biotin probes containing cleavable linkers have been developed to avoid such harsh elution conditions. Lee et al exploited the cyclic acetal moiety as an acid-sensitive linker. Orthoesters, ketals, and acetals are accepted cleavable linkers for drug delivery in vivo. In consideration of long term storage needs in combination with the requirements for stability in physiological conditions and fast cleavage for target identification, Lee et al designed cyclic acetals as acid-cleavable linkers (see for example, pages 8445-8446 and Figure 1). They are readily prepared by simple chemistry from commercially available starting materials. Lee et al introduce the synthesis and capture utility of cyclic acetal linkers in two model systems.
Reference A, Yagnik, and Lee et al do not teach the use of acid-labile (acid-cleavable) linkers to an antibody moiety (Ym).
However, Rady et al teach that cleavable linkers have become the subject of intense study in the field of chemical biology, particularly because of their applications in the construction of antibody-drug conjugates (ADC), where they facilitate lysosomal cleavage and liberation of drugs from their carrier protein. Due to lysosomes’ acidic nature, acid-labile motifs have attracted much attention, leading to the development of hydrazone and carbonate linkers among several other entities. Continuing their efforts in designing new moieties, Rady et al present a family of cyclic acetals that exhibit excellent plasma stability and acid lability, notably in lysosomes. Incorporated in ADC, they led to potent constructs with picomolar potency in vitro and similar in vivo efficacy as the commercially available ADC Kadcyla in mouse xenograft models (see for example, the abstract at page 1860). Cleavable linkers can be defined as chemical groups that can be cleaved in a controlled manner to release at least two distinct molecular entities. The resulting diversity of linker structures has been broadly classified into three main domains, depending on the conditions employed for their cleavage: enzymatic, physicochemical (i.e., photoirradiation), or chemical, the latter being undoubtedly the most populated and diversified group. Linkers sensitive to acidity/basicity, oxidation/reduction, or to nucleophilic species have been thoroughly explored and led to motifs that are now part of the general synthetic chemist toolbox. Interestingly, a second wave of interest in “chemically labile” structures has then emerged with the development of chemical biology in the last two decades, where cleavable linkers are used to connect a payload or a probe to a biomolecule interacting with biological targets. However, the stringent operating conditions imposed by biological environments (e.g., narrow temperature range, aqueous medium, low concentrations, presence of a myriad of biomolecules) have dictated the development of new types of linkers that can be cleaved under milder conditions, typically those found in various intracellular compartments. Indeed, one of the main applications of cleavable linkers in chemical biology resides in the intracellular delivery of compounds of interest, for example, for imaging or therapeutic purposes, which has necessitated the development of chemical moieties with excellent extracellular stability, to avoid premature release and potential off-target delivery of the payload, but rapid and efficient intracellular cleavage. New types of acid-sensitive linkers have been developed for this purpose, to take advantage of the marked differences between the acidity of certain organelles or tissues (e.g., lysosomes or tumor environments, with pH < 5.0), and that of physiological body fluids, with pH ∼ 7.0 on average. However, most of these acid-cleavable linkers also show partial instability in plasma, with half-lives ranging from a few minutes to 2–3 days, leading to risks of early drug cleavage and thus systemic toxicity in vivo. Rady et al, with this issue in mind, synthesized FRET probes, in which a TAMRA fluorophore was linked to a BHQ-2 quencher via known acid-sensitive moieties such as cyclic orthoester motifs or linear acetals (see for example Figure 1 at page 1861). Incubating these probes in different media, Rady et al saw that some were highly stable in human plasma but readily hydrolyzed under acidic conditions, as determined by monitoring the fluorescence intensity of TAMRA. Rady et al became interested in combining motifs from the second and third generation linkers to see the influence of methoxyphenyl groups on the stability of cyclic acetals, in the hope of developing a fourth generation of acetal-based linkers with an improved stability/cleavage balance (see for example, page 1861). Synthesis of FRET probes 5 and 6 incorporating a five-membered (m = 0) and a six-membered (m = 1) ring acetal, respectively (top panel of figure 2). Stability study of FRET probes 5 and 6 at different pH and in human plasma and the measured fluorescence is a direct indication of acetal hydrolysis and, by extension, of linker cleavage (bottom panel of figure 2) (see for example, page 1862). Acetals 5 and 6 were found to be readily hydrolyzed at pH ≤ 4.0 while being stable at neutral pH and in human plasma (see for example, page 1861). To validate that the vesicle-like distribution of TAMRA fluorescence was due to a cleavage in acidic organelles, subsequent incubation of SKBR-3 cells with 2 μM of LysoSensor Green DND-189 was also conducted. To our delight, red and green fluorescence signals seemed to be colocalized as indicated by an orange-yellow fluorescence signal in merged pictures, reinforcing our hypothesis of a lysosomal cleavage. While both probes 5 and 6 led to higher fluorescence values than ValCit probe 7 by flow cytometry analysis, even after only 30 min of incubation, it was interesting to notice that 6 gave systematically a 10-fold increase in fluorescence intensity compared with its five-membered ring homologue 5, a behavior that had not been seen during our stability studies in buffers (Figure 3). On the contrary, linear acetal probe 8 led to barely detectable fluorescence, confirming the microscopy results and its intracellular stability (see for example, page 1862).
Reference A, Yagnik et al, Lee et al, and Rady et al, do not teach the use of a sulfonate precursor, but do teach and motivate the use of an acid to cleave the acetal linker, as noted above.
However, Andraos et al teach that the mechanism of photodissociation (using photoirradiation) and acid generation for three phenolic sulfonate esters, ranging from alkyl, to benzyl, to aromatic, was investigated by laser flash photolysis and product studies. All the sulfonate esters studied showed the presence of phenoxyl and other complex radicals in the transient spectra. The formation of these complex transients indicates that the radical pair formed upon excitation of the sulfonate can escape the solvent cage, and undergo further chemical transformations. It was observed that all of the sulfonate esters investigated resulted in the formation of acidic species. Photoproduct studies indicate that phenyl methanesulfonate and phenyl toluene-p-sulfonate undergo a photo-Fries type rearrangement and also produce a large excess of phenol with the corresponding sulfonic acid. Upon excitation, phenyl toluene-R-sulfonate undergoes near quantitative SO2 extrusion, with the formation of no Fries rearrangement photoproducts; instead it was observed that the benzyl radicals, generated by SO2 loss, undergo a “pseudo” Fries rearrangement to form the ortho and para phenylmethane isomers. Further, the SO2 photogenerated undergoes oxidative and hydrolytic processes to form sulfuric and sulfurous acids (see for example, the abstract at page 1694 and column 2 of page 1695).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because reference A and Yagnik et al teach and make obvious a conjugate having instantly claimed formula I where Yagnik et al further teach photocleavable mass-tags (PC-MTs) for facile antibody labeling, which enables highly multiplexed IHC based on MALDI mass spectrometric imaging (MALDI-IHC) using a laser for photocleavage for imaging of a biological specimen. Rady et al teach that cleavable linkers have become the subject of intense study in the field of chemical biology, particularly because of their applications in the construction of antibody-drug conjugates (ADC), with linkers that are cleavable with acid and/or photoirradiation being known genera in the art. The linkers of Rady et al would have been obvious to use in the conjugate of reference A and/or Yagnik et al because the linkers of Rady et al and the linkers disclosed in reference A and/or Yagnik et al serve the functionally equivalent purpose of linking the antibody and detection moiety. Lee et al teach that acetal linkers are acid-cleavable (acid-labile), making them functionally equivalent linkers for use in the method according to reference A, Yagnik et al, and Rady et al and therefore obvious to use in said conjugate. This makes obvious and motivates the artisan to practice steps a-c of claim 1 with an antibody Y moiety and an acetal P linker of instant formula I. The artisan would have been motivated to use a known means in the art for generating an acid to cleave the acid-labile acetal linker of Lee et al. The artisan would have found the means of Andraos et al to be an obvious methos for acid-generation to try. Andraos et al teach that photoirradiation of a sulfonate (three sulfonates are examiner and shown to degrade to an acid subunit) generates an acid subunit, said acid subunit would have been obvious to use with the conjugate resulting from Lee et al, Rady et al, and Yagnik et al as the acid to cleave the acid-labile acetal linker between the antibody (Y moiety) and the detectable moiety (X). This motivates and makes obvious the practice of steps d-f of claim 1. The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 2, as discussed above, sulfonates, such as the thee sulfonates tested by Andraos et al are cleaved by photoirradiation, presumably into at least 2 subunits (constituent parts), at least one of which being an acid.
Regarding claim 3, as discussed above, the acetal linker (P) is acid-cleavable such that the artisan would expect the acid generated by photoirradiation of the sulfonate to cleave the acetal linker, thereby cleaving the antibody (Y) from the detection moiety (X) by severing their connection to one another. Note also that Rady et al teach cleavage of the detection tag/moiety from the antibody in biomarker/IHC analysis, as discussed above.
Regarding claim 4, Yagnik et al teach the use of photocleavable mass tags (PC-MTs) which comprise an amine-terminal Fmoc-protected version of the photocleavable linker (PC-Linker; red) incorporated during conventional Fmoc-based solid-phase peptide synthesis (SPPS) along with the other amino acids. The example PC-MT shown is oriented with the N-terminal on the left and the C-terminal on the right. “APRLRFYSL” is an example amino acid sequence of the peptide mass unit (see Supplementary Table S1 for all mass units used in this work). The PC-MTs contain a spacer that connects the 1-(2-nitrophenyl)-ethyl-based photocleavable nucleus (PC-Nucleus) to the probe-reactive moiety (see for example, pages 978-979). Yagnik et al also teach that a fluorescent moiety may be used for detection (see for example, column 2 of page 979, pages 981-984, and page 986).
Regarding claim 5, as discussed above, the combined references make obvious the use of an acetal linker (a degradable (interpreted as cleavable given that lack of a closed, preclusive definition of ‘degradable’ in the instant specification)) which is acid-labile/acid-cleavable (this is interpreted to read upon the recitation of the acidic cleavable functional units selected from the group consisting of acetals in the absence of a closed, preclusive definition/description in the instant specification).
Regarding claim 6, as discussed above, the combined references motivate and make obvious a conjugate of instant formula I wherein the Y moiety is an antibody.
Regarding claim 7, as discussed above, the combined references motivate and make obvious the use of a sulfonate precursor to be photoirradiated into an acid subunit for cleaving the acetal linker. This is interpreted to read upon the recitation of the precursor comprising functional units selected from the group consisting of sulfonates in the absence of a closed, preclusive definition/description in the instant specification.
Regarding claim 9, given that the precursor generates an acid, there is a presumed change in the first pH (prior to photoirradiation) and the second pH (after photoirradiation). It is noted that the change in the pH (between a first and second pH) is not an active step, but it instead a result passively achieved by practicing the active steps of claim 1. Therefore, claim 9 is obvious for the same reasons as claim 1 because the result of claim 9 flows naturally from practicing the method of claim 1, as presently drafted.
Claim(s) 8 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of reference A in view of Yagnik et al, Lee et al, Rady et al, and Andraos et al , as applied to claims 1-7 and 9 above, in further view of Zabadal et al (The Journal of Physical Chemistry A 2001 105 (45), 10329-10333 DOI: 10.1021/jp010220e).
Regarding claim 8, as discussed above, reference A, Yagnik et al, Lee et al, Rady et al, and Andraos et al teach and make obvious instant claim 1. Rady et al further teach that linkers sensitive to acidity/basicity, oxidation/reduction, or to nucleophilic species have been thoroughly explored and led to motifs that are now part of the general synthetic chemist toolbox. Interestingly, a second wave of interest in “chemically labile” structures has then emerged with the development of chemical biology in the last two decades, where cleavable linkers are used to connect a payload or a probe to a biomolecule interacting with biological targets. Andraos et al teach that the three sulfonates broke down to form an acid subunit when irradiated at 266nm (see for example, page 1696).
The combined references do not teach a second precursor which is activated at a different wavelength.
However, Zabadal et al teach that irradiation (direct photolysis) of DMP esters at 254−366 nm led to the formation of the free acids in high yields (see for example, the abstract at page 10329 and column 1 of page 10329).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed because the MPEP provides that:
“[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In reKerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In reCrockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine)”,
(see MPEP §2144.06). Here, the 2 precursors (one of the sulfonates from Andraos et al and a of DMP ester from Zabadal et al) activate at two different, non-overlapping wavelengths (the DMP ester activating at 254nm and the sulfonates of Andraos et al activating at 260nm). Both precursors produce an acid and are prima facie obvious to combine for use in the method as claimed because they are taught in the art to be useful for the same purpose of generating an acid upon photoirradiation. The sulfonates of Andraos et al are encompassed by the disclosed genera of precursors and the DMP ester of Zabadal is at the least a functionally equivalent photoacid generating precursor (noting that the only description of precursors is as a compound which is photocleaved/photolysed to provide an acid or base subunit for cleaving the linker (p) in instant formula 1). The wavelength that activates (photocleaves a precursor into an acid or base subunit) is an inherent property which the Office is not in a position to test. It is presumed that the recited genera of precursors would activate at different wavelengths. The MPEP provides that “[a]s a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972) (see MPEP §2113.III). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Claim(s) 10-11 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of reference A in view of Yagnik et al, Lee et al, Rady et al, and Andraos et al , as applied to claims 1-7 and 9 above, in further view of Aichler et al (Lab Invest 95, 422–431 (2015). https://doi.org/10.1038/labinvest.2014.156) and Park (pub. 2021 (as evidenced by ResearchGate); Far UV-C Radiation: Current State-of Knowledge, Downloaded from: https://www.researchgate.net/figure/Penetration-of-UV-wavelengths-into-human-skin-arrows-represent-an-estimate-of-90_fig4_351736833).
Regarding claim 10, as discussed above, the combined references make obvious the method of claim 1 and Yagnik teaches the conjugate for MALDI-IHC imaging of biological matter.
Aichler et al teaches that Matrix-Assisted Laser Desorption Ionization (MALDI) has led the way in the development of biological and clinical applications for imaging mass spectrometry and is therein one of the most commonly used techniques. MALDI imaging has already entered disciplines beside medicine, microbiology as a standard technology for classification or plant pathology for investigating spatially resolved molecular information. This technology provides a broad range of features, which should be recognized by medicine- or pathology-related investigations. The great advantage of MALDI imaging is the correlation of molecular information with traditional histology by keeping the spatial localization information of the analytes after mass spectrometric measurement (see for example, page 422).
Park teaches that photoradiation at wavelengths 200-400nm have a limited penetration, not going beyond the epidermis or dermis, depending on the selected wavelength (see Figure 11 for example at page 17).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references before the effective filing date of the claimed invention. The artisan would have been motivated to make and use the invention as claimed to allow for advantageous correlation of molecular information with traditional histology by keeping the spatial localization information as taught by Aichler et al. It would have been obvious to the artisan to apply the conjugate and the precursor to the surface of the sample because light of 200-400nm had limited penetration (so surface application provides the best likelihood of success for the light to cleave the precursor resulting in acid which must be in proximity with the conjugate to cleave the acetal linker (P)). The artisan would have had a reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 11, the only addition over the method of claim 10 is that there is a first pH (prior to activation of the precursor by application of radiation) and a second pH (after activation of the precursor by application of radiation) the first and second pH differing from one another by at least +/- 0.05. Given that the precursor generates an acid, there is a presumed change in the first pH (prior to photoirradiation) and the second pH (after photoirradiation). It is noted that the change in the pH (between a first and second pH) is not an active step, but it instead a result passively achieved by practicing the active steps of claim 10. Therefore, claim 11 is obvious for the same reasons as claim 10 because the result of claim 11 flows naturally from practicing the method of claim 10, as presently drafted.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO 2020207963 (citation 10 under Foreign Patent Documents on the 05/17/2024 IDS) is deemed relevant.
Suyama et al (Progress in Polymer Science 34 (2009) 194–209) teach that recent progress in photochemical generation of organic bases and its applications to polymer science and technologies are reviewed. Photobase generators (PBGs) have been desired as a novel photolatent catalyst. Several PBGs such as carbamates, O-acyloximes, and ammonium salts have been improved in thermal stability, solubility, multi-functionality, and photo-sensitivity. In addition, new molecular designs including amineimides,-aminoketones, some amidine precursors, and aromatic ureas have been proposed as novel PBGs (see for example, the abstract at page 194). Suyama et al further teach that PBGs appeared above are classified from their original structure and summarized in Table 1 (see for example, column 1 of page 199 and Table 1 at page 200).
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights