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 .
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, and 36 ) in the reply filed on 11/10/2025 is acknowledged.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As set forth in Cephalon Inc. v. Watson Pharmaceuticals Inc. 105 USPQ2d 1817, 1821 (CAFC, 2013):
To satisfy section 112 of the 1952 Patent Act, the specification must enable a person of ordinary skill in the art to make and use the invention. 35 U.S.C. § 112, ¶1. This requirement is met when at the time of filing the application one skilled in the art, having read the specification, could practice the invention without “undue experimentation.” In re Wands, 858 F.2d 731, 736-37 [8 USPQ2d 1400] (Fed. Cir. 1988). Whether undue experimentation is required “is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” ALZA Corp. v. Andrx Pharms., LLC, 603 F.3d 935, 940 [94 USPQ2d 1823] (Fed. Cir. 2010) (citing Wands, 858 F.2d at 737).
The following factors may be considered when determining if a disclosure requires undue experimentation:
(1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Wands, 858 F.2d at 737 (“Wands factors”); Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362, 1372 [52 USPQ2d 1129] (Fed. Cir. 1999) (“The Wands factors, when applied from the proper temporal perspective … are a useful methodology for determining enablement….”). These factors while illustrative are not mandatory. Enzo Biochem, Inc., 188 F.3d at 1371. What is relevant depends on the facts, and although experimentation must not be undue, a reasonable amount of routine experimentation required to practice a claimed invention does not violate the enablement requirement. Id. The burden of proof here is on Watson to show that the Khankari patents are invalid for lack of enablement by clear and convincing evidence. See Auto. Tech. Int'l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 1281 [84 USPQ2d 1109] (Fed. Cir. 2007).
The nature of the invention & the breadth of the claims
Claims 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, and 36 are drawn to a “method, comprising contacting a biological sample with a first probe, wherein the first probe comprises a capture moiety having an oligonucleotide sequence that selectively binds to a RNA in the sample, and a secondary oligonucleotide region that does not bind to the RNA; contacting the sample with a second probe, wherein the second probe comprises a probe binding region that is complementary to, and hybridizes to, a portion of the secondary oligonucleotide region, and comprises a reporter moiety; and extending the secondary oligonucleotide region using the second probe as a template to generate an extended secondary oligonucleotide region comprising multiple copies of the reporter moiety, wherein the reporter moiety comprises a plurality of label regions each comprising an oligonucleotide sequence; and wherein one or more of the label regions of the reporter moiety are different from the other label regions of the reporter moiety”.
The amount of direction or guidance presented
The amount of guidance provided is limited, generally prophetic, and not commensurate with the scope of the claims. The specification provides no working example for the methods recited in claims 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, and 36. Furthermore, there is no experimental condition and/or experimental data in the specification to support the claimed invention.
The presence or absence of working examples
The disclosure does not disclose any examples for the methods recited in claims 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, and 36. From the disclosure, the invention, according to the claims is a method to detect and spatially localizing the RNA in the sample, utilizing a first probe comprises a capture moiety having an oligonucleotide sequence that selectively binds to a RNA in the sample, and a secondary oligonucleotide region that does not bind to the RNA; contacting the sample with a second probe, wherein the second probe comprises a probe binding region that is complementary to, and hybridizes to, a portion of the secondary oligonucleotide region, and comprises a reporter moiety; and extending the secondary oligonucleotide region using the second probe as a template to generate an extended secondary oligonucleotide region comprising multiple copies of the reporter moiety, wherein the reporter moiety comprises a plurality of label regions each comprising an oligonucleotide sequence; and wherein one or more of the label regions of the reporter moiety are different from the other label regions of the reporter moiety. The method is to result in identifying the reporter moieties in the sample and determining one or more locations of the RNA in the sample based on the one or more identified reporter moieties.
However, the detailed description lacks specific embodiments, and the concept is merely explained in the Figures. Said first probe, second probe, reporter, labels, etc. encompass a wide range of oligonucleotide sequences and chemical structures, and it is unclear what kind of sequence enables the above-mentioned binding/hybridization. Therefore, a person skilled in the art will have to perform excessive trial and error to find
a first probe, second probe that actually functions.
Level of Skill in The Art, The Unpredictability of The Art, and The Quantity of Experimentation Necessary
While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether the methods recited in claims 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, and 36 can be performed when the first probe, second probe, reporter, labels, etc. encompass a wide range of oligonucleotide sequences and chemical structures, and it is unclear what kind of sequence enables the above-mentioned binding/hybridization.
The specification teaches (see application’s PG Publication US 20220364160):
[0082] In some embodiments, the hybridization region between first probe binding region 440 and a portion of secondary oligonucleotide region 410 is 10 nucleotides or more (e.g., 15 nucleotides or more, 20 nucleotides or more, 25 nucleotides or more, 30 nucleotides or more, 40 nucleotides or more, 50 nucleotides or more, 60 nucleotides or more, 70 nucleotides or more, 80 nucleotides or more, 90 nucleotides or more, 100 nucleotides or more, or even more). In general, the hybridization region between second probe binding region 450 and a portion of secondary oligonucleotide region 410 can be any of the lengths discussed above in connection with the hybridization region between first probe binding region 440 and a portion of secondary oligonucleotide region 410. The two hybridization regions can be the same length or different lengths.
[0008] The second probe can include a circular nucleic acid. Extending the secondary oligonucleotide region can include performing a rolling circle amplification reaction to extend the secondary oligonucleotide region. The extended secondary oligonucleotide region can include at least 10 copies (e.g., at least 50 copies, at least 100 copies) of the reporter moiety.
[0009] The reporter moiety can include at least 3 label regions (e.g., at least 4 label regions). One of the label regions of the reporter moiety can be different from the other label regions of the reporter moiety. Two of the label regions of the reporter moiety can be different from the other label regions of the reporter moiety. The reporter moiety can include at least two different types of label regions, where each different type of label region has a unique oligonucleotide sequence. The reporter moiety can include at least three different types (e.g., at least four different types) of label regions. Each of the label regions in the reporter moiety can be a different type of label region. Each label region can include at least 15 nucleotides (e.g., at least 30 nucleotides). Each label region can include a same number of nucleotides.
[0069] A target nucleic acid may be any nucleic acid of interest (e.g., RNA or DNA, or a modified nucleic acid). In some embodiments, the target nucleic acid is a coding RNA (e.g., messenger RNA (mRNA)) or a non-coding RNA (e.g., transfer RNA (tRNA), ribosomal RNA (rRNA), microRNA (miRNA), mature miRNA, immature miRNA, small nuclear RNA (snRNA), or long noncoding RNA (lncRNA)). In some embodiments, the target nucleic acid is a splice variant of an RNA molecule (e.g., mRNA, pre-mRNA). The target nucleic acid may be an unspliced RNA (e.g., pre-mRNA, mRNA), a partially spliced RNA, or a fully spliced RNA.
[0155] As used herein, the terms “nucleic acid” or “polynucleotide” refer to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologues, SNPs, and complementary sequences as well as the sequence explicitly indicated.
[0247] The hybridization and signal detection methods, compositions, and kits described herein can be used to detect many different types of RNAs in a wide variety of different samples. The methods, compositions, and kits do not depend on the manner in which RNAs in the sample bind to probes, nor do they depend on the nature of the RNAs. Further, other than the aspects of the label regions described herein, probes can have a wide variety of different structural compositions and functionalities. Provided they do not interfere with the hybridization of optical labels, additional structural features of the probes can be present without interfering with the methods described herein.
[0248] Samples to which the methods, compositions, and kits can be applied include tissue samples (e.g., tissue sections), including fresh, fresh-frozen, and formalin-fixed, paraffin-embedded (FFPE) samples. Other samples include, but are not limited to, cell and tissue lysates, body fluids (e.g., blood, urine, saliva, lymph fluid, renal fluid, and other such fluids), thick tissue (e.g., solid tumor tissue, biopsy samples), individual cells, suspensions of cells and other biological materials, and aspirated samples.
Because it is common technical knowledge that the effects of chemical bonding and enzyme activity, such as the effects on the hybridizing ability and polymerase activity of a compound, are difficult to predict, the quantity of experimentation needed to make or use the invention based on the content of the disclosure (since there are no working examples), is very high and burdensome.
Case law has established that "(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without 'undue experimentation'." In re Wright 990 F.2d 1557, 1561.
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that "[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art". The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. In cases involving predictable factors, such as that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws… In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.
Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that "[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement".
In view of the breadth of scope claimed, the limited guidance provided, the unpredictable nature of the art to which the claimed invention is directed, and in the absence of convincing evidence to the contrary, the claims are deemed to be non-enabled by the disclosure.
In view of the above analysis and in the absence of convincing evidence to the contrary, claims 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, and 36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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.
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) 1-3, 6-7, 10, 12, 14, 17, 20-26, 28-30, 32-34, and 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Desai et al. (WO 2018175779, The paragraphs in the rejection are based on its US 20200224243 equivalent).
Desai et al. discloses a method named PLISH whereby a sample containing target RNA molecules is contacted with a first probe hybridizing to the target RNA and having a section which does not hybridize to said RNA (HR probe). Thereto a second probe hybridizes (Circle) which also comprises reporter moieties (this is viewed to be inclusive of claim 10). Following extension of the first probe, an extended product is generated that comprises a plurality of label regions each comprising an oligonucleotide sequence. The label regions on the same circle may thereby be different (this is viewed to be inclusive of claim 12). Desai et al. further discloses a third and fourth probe being used to generate a circular nucleic acid for rolling circle amplification. (See Fig. 1 A; claims 1, 25-28).
Desai et al. discloses a target site is a complementary region of the target nucleic acid to which a probe binds. A pair of probes in a probe set bind to a pair of different target sites that are sufficiently close together to allow simultaneous hybridization to a bridge oligonucleotide [0078] (this is viewed to be inclusive of instant claim 2: “the second probe comprises a second probe binding region that is complementary to, and hybridizes to, a second portion of the secondary oligonucleotide region different from the first portion of the secondary oligonucleotide region”)
With regards to claims 3 and 6, Desai et al. discloses a circle oligonucleotide comprises a first portion that hybridizes to a complementary region at the 5′ end of the 5′ overhang region of the first probe of a probe set, and a second portion that hybridizes to a complementary region at the 3′ end of the 3′ overhang region of the second probe of the probe set. Circular DNA forms where any two probes of a probe set bind sufficiently close to each other on one of the target nucleic acids to allow ligation of a bridge oligonucleotide and circle oligonucleotide that are hybridized to the two probes to generate a closed circle [0081]-[0082].
With regards to claims 14 and 17, Desai et al.’s FIG. 1C shows that up to five distinct transcripts can be simultaneously detected using five different barcode sequences (one unique sequence for each RNA), and five complementary imager oligonucleotides that are conjugated to spectrally-distinct fluorophores. Desai et al. discloses “A target site is a complementary region of the target nucleic acid to which a probe binds. …. Target sites are typically present on the same strand of the target nucleic acid in the same orientation. Target sites are usually selected to provide a unique binding site not present in other nucleic acids in the sample. Each target site is generally from about 18 to about 30 nucleotides in length, or any length within this range such as 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.[0078] (see also [0144]:PLISH represents a practical technology for multiplexed expression profiling in tissues. It combines high performance in four key areas: specificity, detection efficiency, signal-to-noise, and speed. The specificity derives from coincidence detection, which requires two probes to hybridize next to one another for signal generation. Efficient detection of low-abundance transcripts is accomplished by targeting multiple sites along the RNA sequence. Enzymatic amplification produces extremely bright puncta and allows many different RNA transcripts to be marked with unique barcodes in one step. The different RNA transcripts can then be iteratively detected to rapidly generate high dimensional data).
With regards to claim 21-24, 28-30, 36, Desai et al. discloses:
g) contacting each concatemer with one or more imager oligonucleotides, wherein each imager oligonucleotide comprises a detectable label and a nucleotide sequence complementary to one or more sites in the circular DNA sequence, wherein the imager oligonucleotide binds to said sites in the multiple copies of the circular DNA sequence of the concatemer; (viewed as the instant plurality of optical labels in claim 21 (a) and (b)); and h) detecting the bound imager oligonucleotides (viewed as the instant claim 21 (d)) [0008]. See also [0021] teaching: In another embodiment, subsets of the target nucleic acids are detected sequentially by a method comprising: a) contacting the sample with a subset of the imager oligonucleotides; b) performing a cycle of fluorescence imaging; c) removing the imager oligonucleotides from the sample (this is viewed to be inclusive of claim 36); d) contacting the sample with another subset of the imager oligonucleotides; e) performing another cycle of fluorescence imaging; and f) removing the imager oligonucleotides from the sample. The method may further comprise repeating steps (a)-(f) until all of the imager oligonucleotides have been used for detection of the plurality of target nucleic acids (this is viewed to be inclusive of claims 28-30).
Desai et al. discloses the sample is optionally washed to remove excess imager oligonucleotides. The target nucleic acids are detected by measuring a signal from the bound imager oligonucleotides. The sample can be imaged to reveal the location of the detectably labeled imager oligonucleotides complexed with the target nucleic acids [0068] (viewed as the instant claim 21 (e) and claim 24).
Exemplary detectable labels include fluorescent labels, bioluminescent labels, chemiluminescent labels, isotopic labels, nanoparticles, and metals [0012] (this is viewed to be inclusive of claims 22-23).
With regards to claims 25-26, Desai et al. discloses: In another embodiment, a plurality of probe sets comprising probes capable of hybridizing at a plurality of target sites on multiple target nucleic acids are used for multiplexed detection of a plurality of target nucleic acids. The method may further comprise using a plurality of circle oligonucleotides, wherein each circle oligonucleotide binds to a different probe set; and a plurality of imager oligonucleotides, wherein each imager oligonucleotide comprises a different detectable label. For example, each circle oligonucleotide may comprise one or more binding sites for a different imager oligonucleotide, such that different circle oligonucleotides are bound by different imager oligonucleotides comprising different detectable labels to allow different target nucleic acids to be detectably distinguished from one another [0011].
With regards to claims 32-34, Desai et al. discloses: FIGS. 3A-3D show multiplexed PLISH: rapid label-image-erase cycles, automated data analysis, and unsupervised cell classification. FIG. 3A shows the multiplexed PLISH experimental workflow. Probes for many different RNAs are hybridized and amplified in a single reaction. The PLISH amplicons marking four RNA species are then labeled with four fluorescent imager oligonucleotides, imaged on a microscope, and ‘erased’ by elimination of the imager oligonucleotides. Amplicons marking a different subset of four RNAs are then labeled with four new imager oligonucleotides, imaged, and erased. This cycle is repeated until all of the RNA species have been visualized and photo-documented. The images are automatically aligned and processed, and the signal for each RNA species in each cell is summed to produce single-cell expression profiles. [0033] . For multiplex assays, each RNA species can be detectably labeled in a unique color by using imager oligonucleotides with spectrally-distinct fluorophores. Fluorescence micrographs can be interpreted by direct visual inspection. Typically, up to five distinct channels can be simultaneously detected and imaged by conventional fluorescence microscopy, as well as allowing a determination of RNA abundance. [0097]. In certain embodiments, RNA species are imaged in sets of 5, with differently colored fluorophores associated with different targets (most fluorescence microscopes can only accommodate 5 color channels). In order to overcome the limit of 5 color channels on a typical fluorescence microscope, iterative rounds of staining, imaging and erasing can be used to colocalize large numbers of distinct RNA species in sequential images.[0100]
With regards to claims 7 and 20, they merely cover embodiments that fall into the range of the conventional for the skilled person.
With regards to claim 7, Desai et al. discloses f) performing rolling circle amplification, wherein each circular DNA molecule formed serves as a template to produce a concatemer comprising multiple copies of the circular DNA nucleotide sequence (this is viewed to be inclusive of at least 10 copies); g) contacting each concatemer with one or more imager oligonucleotides, wherein each imager oligonucleotide comprises a detectable label and a nucleotide sequence complementary to one or more sites in the circular DNA sequence, wherein the imager oligonucleotide binds to said sites in the multiple copies of the circular DNA sequence of the concatemer; and h) detecting the bound imager oligonucleotides ([0008] and claim 1).
With regards to claim 20, Desai et al. discloses “The terms “polynucleotide,” “oligonucleotide,” “nucleic acid” and “nucleic acid molecule” are used herein to include a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides” [0047]; “As used herein, the term “probe” or “oligonucleotide probe” refers to a polynucleotide, as defined above, that contains a nucleic acid sequence complementary to a nucleic acid sequence present in the target nucleic acid analyte. The polynucleotide regions of probes may be composed of DNA, and/or RNA, and/or synthetic nucleotide analogs. Probes may be labeled in order to detect the target sequence. Such a label may be present at the 5′ end, at the 3′ end, at both the 5′ and 3′ ends, and/or internally” [0056].
Therefore, one of ordinary skill in the art seeking to solve the stated problem, according to the circumstances, would have been motivated to modify the primary reference in the manner of the claims, without exercising inventive skill, to achieve the expected benefits, optimizations and/or expanded applications as this is well known practice in the art.
MPEP states wherein the “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Alter, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Routine optimization is not considered inventive and no evidence has been presented that the selection for the number of copies of the reporter moiety or for the label regions comprising a same number of nucleotides, was other than routine, that the products resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEZIA RILEY whose telephone number is (571)272-0786. The examiner can normally be reached 7:30-6:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEZIA RILEY/Primary Examiner, Art Unit 1681 30 January 2026