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 1-20 are pending and under examination on the merits.
Priority
Applicant’s claim of priority to U.S. Provisional Application No. 63/434,263, filed 12/21/2022, is acknowledged.
Claim Rejections - 35 USC § 112
35 USC § 112(a)
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 1-20 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
Independent claim 1 is directed to an aptamer-based biosensor with dependent claims adding features of the biosensor.
Independent claim 11 is directed to a method of using a biosensor having the components claim 1.Claims 12-20 add features of the method of claim 11.
The claims generically recite the genera of an aptamer (capable of binding the compound of interest), a trigger (capable of binding the aptamer and the sensing sequence region), a sensing sequence region/sensor (a nucleic acid molecule undergoing a conformation change from a non-reporting to a reporting stage upon binding of the trigger to the sensing sequence region/sensor (see for example, pages 4 and 6 of the specification)), and a compound of interest. There is no structure provided for the aptamer, trigger, sensing sequence region/sensor, or for a compound of interest. Therefore, there is no clearly disclosed structure-function correlation. Applicant does not provide any defined species of aptamers, triggers, or sensing sequence regions/sensors for consideration. Applicant discloses the species of Kanamycin, Apramycin, Gentamycin, streptomycin, cocaine, and ampicillin (see Figs. 6-9) for genus of a/the compound of interest. The genus of a compound of interest is not given a closed definition. This genus encompasses broad and diverse biological classes such as small molecules, cells, antibodies, nucleic acids, proteins, etc.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has not disclosed any structure or species for the aptamer, trigger, or sensing sequence region/sensor and has only disclosed the species of the compound of interest of Kanamycin, Apramycin, Gentamycin, streptomycin, cocaine, and ampicillin (see Figs. 6-9). Thus, given the substantial structure variation within the genera as well as the high level of unpredictability in the art, the disclosure of either no species (for the aptamer, trigger, and sensing sequence region) or four species (for the compound of interest) is not sufficiently representative of the entire genus/genera.
Although screening techniques can be used to isolate variant polypeptides (and the vectors/nucleotides encoding them) that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Applicant is further directed to In re Alonso (545 F.3d 1015 (Fed. Cir. 2008), which involved claims that were directed to methods of using antibodies wherein the court found that the claims lacked adequate written description for the recited genus of antibodies recited in the methods. (C) See p. 8, 3rd paragraph, where Applicant argues that the claims recite all essential features of the invention. Therefore, products used in methods are rightfully subject to the written description requirement.
Regarding the state of the art for aptamers, Lee et al (Biomedicines. 2023 Jan 26;11(2):356. doi: 10.3390/biomedicines11020356) teach that most aptamers are developed via in silico design and that, while aptamers can be designed that bind to complex polymers such as small molecules or proteins, with the current technology level, it is impossible to design aptamers that bind to cells (see for example, page 2 of 22). Likewise, Bruno et al (Molecules. 2015 Apr 16;20(4):6866-87. doi: 10.3390/molecules20046866) teach that, while there are rare cases in which one can engineer effective bidentate or multidentate aptamers, if detailed knowledge of proximal epitopes and their spacing on complex targets is available, but in general, natural selection will probably produce superior affinity or avidity and specificity (see for example, section 2.1 at page 6869). Moreover, Chen et al (Nat Biotechnol 40, 1601–1609 (2022). https://doi.org/10.1038/s41587-022-01337-8) teach that, since the appreciation of mirror aptamers’ biochemical advantages over two decades ago, mirror-image aptamers have been selected primarily through an indirect scheme known as ‘selection-reflection’: the mirror-image version of the target molecule is first chemically synthesized for the selection of a natural aptamer, after which a mirror-image aptamer with the same sequence is synthesized to bind the corresponding natural target. However, the first step of chemically synthesizing the mirror-image target molecule is often problematic, especially for proteins with large sizes, extensive posttranslational modifications (PTMs) and low in vitro folding efficiencies. In practice, most biologically important target molecules such as large proteins cannot be chemically synthesized based on current technologies. As a result, only a small number of mirror-image aptamers have been discovered by selection-reflection thus far, largely restricted to targeting small molecules, short peptides, short RNAs, and small proteins with the largest being a 110-amino acid (aa) ribonuclease from Bacillus amyloliquefaciens (barnase) at 12 kDa. Selections of mirror-image aptamers targeting most biologically important and yet unsynthesizable target molecules have not been realized. It is established in the art that single point mutations are not independent from each other and the interactions between an aptamer and its target depend upon an intricate structure dictated by its sequence (Hasegawa et al Molecules 2016, 21(4), 421 pg. 1-15; https://doi.org/10.3390/molecules21040421, at, for example, page 3 at paragraph 2). Thus, mutations of aptamers can yield unpredictable results. Aptamers fold into unique structures that usually include stems and loops (Hasegawa, page 3, first paragraph). These structures are central to target molecule recognition and any disruptions result in poor binding abilities (see for example, Hasegawa et al, page 3, paragraph 2). Mutagenesis studies of IgE-binding aptamers showed point mutations at most positions within IgE aptamer sequences readily decreased the binding ability of aptamers (see for example, Hasegawa et al at page 2, last paragraph to page 3, first paragraph).
Furthermore, aptamers are traditionally generated solely on the basis of their ability to bind strongly to a specific target. Most aptamer-based switches must undergo a conformational change in order to generate an output in response to target binding, but affinity-based selection is generally unlikely to produce aptamers that innately exhibit such behavior. As such, it has generally proven necessary to engineer such functionality into newly isolated aptamers, thereby conferring the ability to selectively respond to an external trigger. One such example employed a widely utilized cocaine aptamer, in which one stem of its three-way junction structure was shortened in order to introduce instability, allowing for the transition to the bound state by ligand-dependent stabilization of the binding pocket. However, the majority of aptamers are not as easily converted to switches, and different mechanisms have been employed to establish this capability (see for example, section 2 at page 2 of 26 of Rangel et al (Adv. Mater.2020, 32, 2003704, https://doi.org/10.1002/adma.202003704)). It is noted that, while the provisional US Application claims a single-stranded nucleic acid trigger, the specification defines a trigger as annealed DNA (see for example, page 5). The sensing sequence region/sensor (understood to be synonymous with the sensing strand) is defined as a nucleic acid molecule (see for example, page 6 of the specification). The definitions of the trigger and sensing sequence region/sensor encompass dsDNA, ssDNA, ssRNA, and aptamers. As noted above, aptamers are highly unpredictable, particularly where a conformation change (as between a reporting and non-reporting configuration) and binding interaction are unpredictable. The trigger must be capable of binding both the aptamer and the sensing sequence region. The sensing sequence region/sensor must be capable of being bound by the trigger and of undergoing a change between a reporting and non-reporting configuration.
Regarding the state of the art of compounds of interest, as noted above, the state of the art supports the unpredictability of designing aptamers, particularly mirror aptamers, for binding different compounds of interest.
Therefore, the genera of claimed aptamers, triggers, sensing sequence regions, and compounds of interest are insufficiently described through a demonstrated correlation of a conserved/identifying structure with the claimed function(s) or through a representative number of species. The disclosure amounts to a suggestion for the artisan to screen for or design as-of-yet undiscovered structures for use in the proposed arrangement. "One cannot describe what one has not conceived,” (see Fiddes v. Baird, 30 USPQ2d 1481 at 1483). In Fiddes, claims directed to mammalian FGF' s were found to be unpatentable due to lack of written description for that broad class.
Therefore, claims 1-20 are deemed to fail to meet the written description requirement, as presently drafted.
Conclusion
No claim is allowed.
Notice:
The closest prior art is either Feagin et al (ACS Sens. 2018 Sep 28;3(9):1611-1615. doi: 10.1021/acssensors.8b00516. Epub 2018 Aug 29. PMID: 30156834) or Stojanovic et al (WO2017210683A1). Feagin et al teach a variety of prior art means for designing an aptamer biosensor that can switch its structure upon target binding offers a powerful strategy for molecular detection. Stojanovic et al teach a "pseudo-sandwich assay" in which a sample to be tested for the presence and/or amount of an analyte of interest is contacted with effective amounts of (1) a primary aptamer comprising a core sequence that binds to the analyte as well as at least a portion that is complementary to a structure -switching "sensor oligonucleotide"; (2) a sensor oligonucleotide, optionally bound to a solid support, which optionally further comprises a portion complementary to a "comp" (for "complementary") oligonucleotide; wherein the primary aptamer and/or sensor oligonucleotide and/or comp oligonucleotide comprise a detectable moiety(ies) which can detect whether the primary aptamer and sensor oligonucleotide are bound to each other or unbound; and wherein the primary aptamer and sensor oligonucleotide form a partially double stranded helix that detectably dissociates, or does not form, when the primary aptamer is bound to analyte. For example, a test sample may be added to an effective amount of complexes comprised of primary aptamer and sensor oligonucleotide and comp oligonucleotide; the amount of primary aptamer released from the complexes correlates with the amount of analyte in the test sample (and the comp and sensor oligonucleotides form an at least partially double-stranded structure) (see for example, pages 2-3).
However, the presently claimed biosensor of claim 1 requires an aptamer complexed with a displaceable trigger, said trigger decoupling from the aptamer upon aptamer-target/compound of interest binding. The displaced trigger then binds to the sensor causing a detectable signal. There is no teaching in the art which reasonably suggests this arrangement comprising a trigger which binds to aptamer, decouples, and then binds to the sensor. The art does, however, suggest a high degree of unpredictability in the art (see for example, the teachings and references cited in the rejection under 35 USC 112(a) as well as Feagin et al which teaches that the process of converting an aptamer into a “structure-switching” biosensor is challenging and often relies on trial-and-error without established design principles (see for example, the abstract at page 1611). Therefore, the apparatus/biosensor of claim 1 is deemed to be free from the prior art. Claims 2-10, incorporating via dependency from claim 1, the novel subject matter of claim 1 are also deemed to be free from the prior art. The method of claim 11 is clearly limited to a biosensor comprising the recited components in the recited arrangement of claim 1 and is therefore, likewise, deemed to be free from the prior art as are its dependent claims 12-20, which incorporate said novelty via dependency from claim 11. It is noteworthy that, where the unpredictability of the art is high, the prior art must step in to provide a rationale for obviousness including provision of a reasonable expectation of success. No such teaching appears in the prior art.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights