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 .
Status of the claims
Applicant’s amendments filed 04/03/2026 is acknowledged and entered. Claims 1-12, 14-18, 21 and 23-27 are pending and claims 9-10 and 23 are withdrawn. See the office action of 07/10/2025 for the withdrawal of claims 9-10 and 23 as being directed to non-elected invention.
Therefore, claims 1-8, 11-12, 14-18, 21 and 24-27 are examined on merits in this office action.
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 1-8, 11-12, 14-18, 21 and 24-27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "wherein the first organelle and the second organelle are different". The recitation is confusing and does not provide clarity regarding what is intended to encompass. As recited in the preceding lines of the paragraph, both the first organelle and the second organelles encompass the same types of organelles and when they are recited with the same types of organelles, how they are different. As for example, mitochondria are recited for first organelle and mitochondria is recited for the second organelle. Then how are they different? If the recitation is intended for the first organelle in the first complex is different from the second organelle of the second complex, then Applicant is clearly reciting so to clearly and distinctly claim what is intended to encompass in the claim. If that’s what Applicant is intended to encompass in the claim, then the specificity of first probe and the second probe is in question. Are they specific to distinct organelle or specific to the same organelle on different epitopes or specific to same organelle from cells from different species of animal (mixture of cells) as the sample is not clearly defined in the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-8, 11-12 and 14-18, 21 and 24-27 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over of Sood et al (US 2015/0099650A1) in view of Tom-Moy (US 2009/0142,775A1).
In regards to claims 1 and 4, Sood teaches method of probing and analyzing multiple targets in a biological sample using plurality of probes (Abstract). Sood teaches adhering (i.e. depositing) biological sample to membranes (i.e. solid support) and probed sequentially (paragraph [0141]). Sood teaches immobilization of biological targets on a solid support and subsequently detected (paragraph [0048]; [0053], [0034] and [0094]). Sood teaches providing biological sample containing multiple targets and binding a set of probes to the multiple targets, thereby forming complex, wherein two or more of the probes comprise independently a binder capable of specific binding to at least one target in the biological sample, a signal generator (SG), a linker which couples the SG to the binder, and a masking agent coupled to the SG which quenches the signal of the SG. Sood teaches detecting at least one signal from at least one signal generator from at least one signal generator from the set of probes. Subsequent to the step, Sood teaches contacting the sample comprising the bound probes with a chemical agent, electromagnetic radiation or a combination thereof and simultaneously deactivating the at least one signal generator by cleavage of a linker bound to the signal generator and activating at least one signal generator from the set of probes previously quenched by a masking agent and detecting at least one signal from the activation of the at least one newly activated signal generator (claim 1). Sood teaches that the signal generators are fluorescent dyes (claims 4-8).
Sood does not specifically mention forming complex with organelles on cell sample.
Tom-Moy teaches separating organelles using probe the specifically binds to different types of organelles (Abstract). Tom-Moy teaches affinity probe that selectively binds to specific type of organelles wherein the affinity probe is an antibody (para [0014] and claim 9).
Therefore, giving the teaching of Tom-Moy that antibody can be used as a probe to target different types of organelles (Tom-Moy) and given the fact that Sood is directed to probing multiple targets in biological sample and throughout the specification teaches that biological sample includes cell organelles (paragraph [0026]), it would be obvious to one of ordinary skilled in the art to easily envisage providing antibody directed to organelles for probing and analyzing organelles with a reasonable expectation of success. Sood teaches that in some embodiments, a biological sample may include a tissue sample or section, or a whole cell, a cell constituent, e.g. a cell organelle (paragraph [0090]). Therefore, Sood clearly envisage organelles as target for probing in the sample. Therefore, immobilization of tissue sample and probing organelles of cell are obvious from the disclosure of Sood. Moreover, one of ordinary skilled in the art would also envisage probing of organelles inside cells or probing after lysis of the cells with antibody specific to organelles.
In regards to claims 2-3, Sood teaches the first and second fluorescent dyes are spectrally distinct (paragraph [0072]).
In regards to claims 5-8 and 27, Sood teaches various cleavable linkers and cleavable agents (Table 2) including photocleavable linkers (paragraph [0167] and Table 1) and having disulfide and hydrazone linkers (paragraphs [0170]-[0171]) and the linkers have covalent bonds (i.e. covalent linker).
In regards to claim 11, Sood teaches biological sample include frozen tissue (paragraph [0900]) and tissue sample fixed and embedded in parffin (Paragraph [0137]).
In regards to claims 15-16 and 24-27, Sood teaches that a target may include a nucleic acid and the binder may include a complementary nucleic acid including nucleic acid outside of cells (paragraph [0026]) and thus detection of various targets of multiple targets including various process of detection of detectable label would be obvious to one of ordinary skilled in the art absent showing of unexpected advantages with a particular detection process.
In regards to claims 14 and 18, Sood teaches fluorescent morphological stains (and their target cells, subcellular compartments, or cellular components) may include fluorescein-phalloidin (para [0158]) for staining actin fibers, which also makes obvious of determining the morphology of cell.
In regards to claim 17, Sood teaches plurlality of sets of probes and teaches various binders as for example, antibody, small molecule binder, aptamer (paragraphs {0020], [0050], [0057],[0083],[107]) including conjugates of immunoglobulins (para [0021]). Therefore, since the basic concept has been provided by Sood for sequential detection of analytes, use of various types of binders including conjugates of antibody with oligonucleotide wherein oligonucleotide is replaced with detectable moiety fluorophoes in the conjugate, would be obvious to one of ordinary skilled in the art absent showing of unexpected advantages of utilizing a particular binder.
In regards to claim 21, Sood teaches that a biological sample include a tissue sample or section, a whole cell, a cell constituent, e.g. a cell organelle, a cytospin or a cell smear (para [0090] and [0026]). Sood teaches detection of actin fibers (para [0158]) including fluorescent probe (fluorescein-phalloidin) for specific binding to actin fibers (para [0158]).Therefore, given the fact that Sood teaches the basic concept of detection of various macromolecules including various organelles utilizing first fluorescent probe and second fluorescent probe and since Sood discloses a specific fluorescent probe that targets actin fibers, various probes and detection of various organelles including endoplasmic reticulum would be obvious to one of ordinary skilled in the art.
Response to argument
Applicant's arguments filed 04/20/2026 have been fully considered but are not found persuasive to overcome the rejection under 35 USC 103. Moreover, Applicant’s amendments necessitated modifying the rejection under 35 USC 112 (b) as described above.
In regards to arguments for rejection under 35 USC 103, Applicant argued that the following elements are missing from both Sood and Tom-Moy:
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Applicant argued that there is no explicit suggestion in either reference to use a mixed strategy where one organelle is probed with a cleavable-linker dye, and another with a non-cleavable dye, and then to image sequentially before and after cleavage. Thus, although some of the components exist separately in the references, the specific combination and sequencing of steps in the present claims is not expressly or implicitly taught by the combination of Sood and Tom-Moy.
The above arguments have fully been considered but are not found persuasive. The recitation “fluorescent dye attached to second probe via a covalent linker”, does not make the linker non-cleavable, as asserted by Applicant and the recitation does not make the non-cleavable linker not having any covalent bonds. Cleavage of a linker depends of the condition and specific chemical utilized for the cleavage. As for example, a polypeptide having a specific enzyme site (protease cleavage site) comprises amino acids linked via peptide bonds (covalent bonds) and the cleavage depends on the presence of specific amino acid at the cleavage site. The linker having the protease site is cleavable by protease enzyme having specific condition, but not by other enzymes or other conditions. Thus, cleavable linker may be non-cleavable in other conditions and the recitation of “covalent linker” does not make it non-cleavable as discussed above. Therefore, without clearly defining the linker composition and by reciting “cleavable linker” and “covalent linker”, the linker are not distinguishable from the other. Moreover, Applicant’s assertion that claim recites “detecting the first dye, cleaving linker, and then detecting the second dye remaining on a different organelle” does not have support in the claims as the claims are not limited to first probe and the second probe having binding specificity to organelles and forming complex with different organelles. Contrary to Applicant’s assertion, as amended, both the first organelle and the second organelle comprises the same types of organelles.
According to MPEP 2145 “Consideration of Applicant's Rebuttal Arguments,” arguing limitations which are not claimed is improper:
“Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In reVan Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993) (Claims to a superconducting magnet which generates a “uniform magnetic field” were not limited to the degree of magnetic field uniformity required for Nuclear Magnetic Resonance (NMR) imaging. Although the specification disclosed that the claimed magnet may be used in an NMR apparatus, the claims were not so limited.); Constantv. Advanced Micro-Devices, Inc., 848 F.2d 1560, 1571-72, 7 USPQ2d 1057, 1064-1065 (Fed. Cir.), cert. denied, 488 U.S. 892 (1988) (Various limitations on which appellant relied were not stated in the claims; the specification did not provide evidence indicating these limitations must be read into the claims to give meaning to the disputed terms.); Ex parteMcCullough, 7 USPQ2d 1889, 1891 (Bd. Pat. App. & Inter. 1987) (Claimed electrode was rejected as obvious despite assertions that electrode functions differently than would be expected when used in nonaqueous battery since “although the demonstrated results may be germane to the patentability of a battery containing appellant’s electrode, they are not germane to the patentability of the invention claimed on appeal.”).
Regarding Applicant’s argument that in Sood, every probe is cleavable and in contrast, present claim requires a first probe with a cleavable linker and a second probe with a covalent linker, it is noted that “second probe via a covalent linker” does not exclude that the second probe is not cleavable and claim does not recite so. Moreover, cleavable linkers include covalent linkages (see paragraph [0243] of the specification (i.e. can be considered as covalent linkers). Thus claim 1 encompass covalent linkers for both the first and second probe as recitation “covalent linker” does not exclude cleavable linker. Moreover, as described above, cleavage depends on the nature and cleaving conditions and thus without clear structure or specificity of cleaving chemistry and composition of the linkers, various covalent linkers are includes in the cleavable linker.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHAFIQUL HAQ whose telephone number is (571)272-6103. The examiner can normally be reached on Mon-Fri 8-4:30.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory S. Emch can be reached on 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SHAFIQUL HAQ/
Primary Examiner, Art Unit 1678
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