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 with traverse of Group I and species in the reply filed on 01/05/2026 and 05/04/2026 is acknowledged. The traversal is on the ground(s) that claims 92-94 of Group II fall within the scope of the claims identified by Group I and that Restriction was respectfully improper. This is not found persuasive because the invention of Group II has a different design and different steps.
The requirement is still deemed proper and is therefore made FINAL.
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 73-84, 86-88, 90-91 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.
Claims 73, 74 are vague and indefinite with respect to what constitutes the metes and bounds of “product thereof”.
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 73-84, 86-88, 90-91 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
Claim 73-84, 86-88, 90-91 are drawn to a generic “method for analyzing a biological sample comprising contacting the biological sample with an oligonucleotide comprising a hybridization region complementary to a target, a photoactivable functional moiety capable of covalently bonding to an endogenous molecule in the biological sample” thereby hybridization of said oligonucleotide to the target at a location in the biological sample”. As set forth in claim 73, the sole independent claim under consideration, the method is to result in “detecting a signal associated with a detectable probe at the location in a biological sample”.
Applicant, asserts:
A sample disclosed herein can be or derived from any biological sample… The biological sample can include any number of macromolecules, for example, cellular macromolecules and organelles (e.g., mitochondria and nuclei). The biological sample can be a nucleic acid sample and/or protein sample...
Biological samples can be derived from a homogeneous culture or population of the subjects or organisms mentioned herein or alternatively from a collection of several different organisms…[0170]-[0183]
The oligonucleotide is a probe that comprises one or more DNA bases. In some embodiments, the oligonucleotide is a probe that comprises one or more RNA bases. In some embodiments, the oligonucleotide is a probe that comprises one or more DNA bases and one or more RNA bases. In some embodiments, the probe is a circular probe. In some embodiments, the circular probe is a circularized probe generated from a circularizable probe or probe set hybridized to a nucleic acid (e.g., a genomic DNA, an mRNA, a cDNA, or a probe) in the biological sample… [0155]-[0163].
The endogenous molecule may be a protein, a nucleic acid, a carbohydrate, or a lipid.[0066]
The target molecule may be: i) a DNA concatemer, or ii) an intermediate probe that directly or indirectly binds to a DNA concatemer. In any of the embodiments herein, the DNA concatemer may be a rolling circle amplification (RCA) product (RCP). In any of the embodiments herein, the RCP may comprise a plurality of barcode sequences. In some embodiments, the RCP comprises a barcode sequence corresponding to an analyte or a portion thereof in the biological sample. In any of the embodiments herein, the RCP may be a product of a nucleic acid molecule in the biological sample or a product of a circular or circularizable probe or probe set that hybridizes to the nucleic acid molecule [0008]. The target molecule may be a genomic DNA, mRNA, or cDNA, or a product thereof. In any of the embodiments herein, the target molecule may be a nucleic acid probe that hybridizes to a genomic DNA, mRNA, or cDNA. In any of the embodiments herein, the target molecule may be a nucleic acid probe that hybridizes to a genomic DNA, mRNA, or cDNA [0064]-[0065]
The quantity of experimentation necessary
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the art suggests that there are millions of species of viruses and fungi that are yet to be identified and characterized. Assuming, arguendo, that one were to identify a new virus or fungus every day, 365 days a year, and to also determine in the same day the nucleotide sequence of the genome of said organism, and additionally, identify probes and primers that would be useful in the identification of a target sequence found in said new organism wherein said target sequence has utility under 35 USC 101, it would take approximately 2739 years to sequence even 1 million viruses or fungi. Clearly, such an effort to enable the full scope of that claimed would constitute undue experimentation. In support of this position attention is directed to Cephalon, 1823:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983). Likewise, we have held that the amount of experimentation would be undue where: (1) the specification lacks guidance by teaching away from the subject matter that was eventually claimed; and (2) there is evidence of the patentee's own failures to make and use the later claimed invention at the time of the application. See, e.g., AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244 [68 USPQ2d 1280] (Fed. Cir. 2003)
Alternatively, even if the claimed method was limited to the detection of known organisms, the selection of oligonucleotides and probes would also constitute undue experimentation. In support of this position, it is noted that if one were to utilize a probe or primer that was but 20 nucleotides long, and to then substitute each of the positions with the four common dNTPs, there are some 420, or 1.099 x 1012 different sequences to screen/evaluate. In support of the position that to screen such a number of candidate molecules would constitute undue experimentation, attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1276 (Fed. Cir. June 2013):
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
Our cases have described limits on permissible experimentation in the context of enablement. For example, in ALZA Corp. v. Andrx Pharmaceuticals, LLC, we affirmed a judgment of nonenablement where the specification provided “only a starting point, a direction for further research.” 603 F.3d 935, 941 [94 USPQ2d 1823] (Fed. Cir. 2010) (internal quotation omitted). We concluded that one of ordinary skill “would have been required to engage in an iterative, trial-and-error process to practice the claimed invention even with the help of the … specification.” Id. at 943. In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Here, the specification similarly discloses only a starting point for further iterative research in an unpredictable and poorly understood field. Synthesizing candidate compounds derived from sirolimus could, itself, require a complicated and lengthy series of experiments in synthetic organic chemistry. Even putting the challenges of synthesis aside, one of ordinary skill would need to assay each of at least tens of thousands of candidates. Wyeth's expert conceded that it would take technicians weeks to complete each of these assays. The specification offers no guidance or predictions about particular substitutions that might preserve the immunosuppressive and antirestenotic effects observed in sirolimus. The resulting need to engage in a systematic screening process for each of the many rapamycin candidate compounds is excessive experimentation. We thus hold that there is no genuine dispute that practicing the full scope of the claims, measured at the filing date, required undue experimentation. (Emphasis added).
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 presence or absence of working examples
The disclosure does not disclose any examples.
From the disclosure in paragraphs [0002] - [0005], the invention, according to the claims, may allow for better resolution of signals, resolution of signals associated with different analytes, and/or, improved spatial fidelity and detection during downstream analyses utilizing a molecule comprising a branched linker comprising one or more detectable labels and/or one or more sequences for hybridizing to a detectably labeled probe. However, the detailed description lacks specific embodiments, and the concept is merely explained in the Figures. Here, in view of the disclosure, to perform the method of claim 73, an oligonucleotide of unknown sequence hybridizes to a target of unknown sequence, and said oligonucleotide of unknown sequence needs to hybridize to some region (unknown sequence) and said oligonucleotide of unknown sequence comprises a photocleavable functional moiety, linked to said oligonucleotide via a linker, capable of covalently bonding to an unknown endogenous molecule in a biological sample. Additionally, the detectable probe of unknown sequence can directly or indirectly binds said oligonucleotide or a product thereof (of unknown sequence or structure). It is unclear what kind of sequence enables the above-mentioned hybridization/binding. Because it is common technical knowledge that the effects of chemical bonding, such as the effects on the hybridizing ability 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. Therefore, a person skilled in the art will have to perform excessive trial and error to find a compound for the oligonucleotide and probe that actually function.
The state of the prior art
Prior art teaches of numerous problems confronting those of ordinary skill in the art. These problems have not been addressed by the instant disclosure. Absent specific guidance as to how these issues are to be overcome, one of ordinary skill in the art would be forced to trial-and-error experimentation in an effort to overcome these known issues.
Zhang et al., Bioinformatics, Vol. 19, No. 1, 2003, page 14, states:
It is widely recognized that the hybridization process is prone to errors and that the future of DNA sequencing by hybridization is predicated on the ability to successfully cope with such errors. However, the occurrence of hybridization errors results in the computational difficulty of the reconstruction of DNA sequencing by hybridization. The reconstruction problem of DNA sequencing by hybridization with errors is a strongly NP-hard problem. So far the problem has not been solved well.
Chan (US Patent Application Publication US 2002/0119455 A1):
[0018] In practice, Probe Up methods have been used to generate sequences of about 100 base pairs. Imperfect hybridization has led to difficulties in generating adequate sequence. Error in hybridization is amplified many times. A 1% error rate reduces the maximum length that can be sequenced by at least 10%. Thus if 1% of 65,536 oligonucleotides gave false positive hybridization signals when hybridizing to a 200-mer DNA target, 75% of the scored "hybridizations" would be false (Bains, 1997). Sequence determination would be impossible in such an instance. The conclusion is that hybridization must be extremely effective in order to generate reasonable data. Furthermore, sequencing by hybridization also encounters problems when there are repeats in sequences that are one base less than the length of the probe. When such sequences are present, multiple possible sequences are compatible with the hybridization data. (Emphasis added.)
Barany et al. (US 2007/0042419 A1), at paragraph 0036 teaches in part:
For allele-specific oligonucleotide hybridization ("ASO"), the mutation must be known, hybridization and washing conditions must be known, cross-reactivity is difficult to prevent, closely-clustered sites due to interference of overlapping primers cannot undergo multiplex detection, and mutant DNA cannot be detected in less than 5% of background of normal DNA.
Choi et al. (US 2007/0042400 A1), at paragraph 0035, teach:
[0035] In conventional methods of preparing nucleic acid, polysaccharides such as starch often co-precipitate with nucleic acid. When polysaccharides co-precipitate with nucleic acid, it is difficult to manipulate nucleic acids by amplification methods, such as PCR, or by other detection methods, such as hybridization detection. Polysaccharides may also inhibit digestion with restriction endonucleases and other enzymatic manipulations.
As evidenced above, the art is replete with known issues that directly impact the enablement of the claimed invention. A review of the instant disclosure fails to identify how these art-recognized issues are to be overcome such that the full scope of the invention can be practiced without the public having to resort to undue experimentation.
The predictability or unpredictability of the art
As noted in In re Fisher 166 USPQ 18 (CCPA, 1970):
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.
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 73-84, 86-88, 90-91 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.
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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/JEZIA RILEY/Primary Examiner, Art Unit 1681 25 June 2026
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