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 invention I and the species VHH72 in the reply filed on 6/23/26 is acknowledged.
Claims 45, 46, 55, 56, 69, 70, 74-76, 101, 102, 113, 115, 118 and 120 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/23/26.
Claims 1, 2, 5, 7 and 8 are examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/19/23, 4/15/24 and 6/23/26 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided. Presently, the abstract recites, “e.g.,” and “i.e.,” several times which is interpreted as legal phraseology. It is suggested that applicants use “for example” in place of these phrases.
Claim Interpretation
The examined claims require a fluorogenic small molecule being conjugated to a nanobody.
The specification at paragraphs [036] and [039] state:
[036] The term "fluorogenic small molecule" or "fluorophore" refers to a small molecule capable of emitting absorbed light, i.e., fluorescing. In certain embodiments, a fluorogenic small molecule can increase/decrease in fluorescence (i.e., "turn on") in response to changes in viscosity, polarity, or other physical changes. In some embodiments, the fluorogenic small molecule exhibits a detectable change in fluorescence lifetime.
[039] The term "small molecule" refers to molecules, whether naturally-occurring or
artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight.
Typically, a small molecule is an organic compound (e.g., it contains carbon). The small
molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional
groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain
embodiments, the molecular weight of a small molecule is not more than about 1,000 g/mol,
not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700
g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about
400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than
about 100 g/mol. In certain embodiments, the molecular weight of a small molecule is at least
about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol,
at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800
g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above
ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible.
Therefore, the claims will be examined based on this guidance from the specification.
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, 2, 5, 7 and 8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a fluorogenic sensor specific comprising a VHH72 with a fluorogenic small molecule attached at the binding domain to, which is specific for a SARS-CoV-2 spike protein, does not reasonably provide enablement for a generic nanobody without the 3 CDRs sequences being defined and the target being defined or a variant of a spike protein of a variant of a SARS-CoV-2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The claimed invention is drawn to a fluorogenic sensor comprising a nanobody and a fluorogenic small molecule conjugated at or around a target-binding domain of the nanobody, wherein the sensor is for detecting a target. The nanobody is VHH72 and the nanobody binds to a spike protein of a coronavirus, such as SARS-CoV-2 or a variant thereof.
Applicants teach nanobody VHH72 with a L-(7-hydroxycoumarin-4-yl) ethylglycine (Cou) located at residue 108 of VHH72 and test the ability of this nanobody to bind to the spike protein of SARS-CoV-2.
Thus, the claim is are directed to a broad class of nanobodies, only defined by its function (binding a generic target molecule). However, the specification does not give one of ordinary skilled in the art enough information to choose candidate antigen binding structures from the vast number of options that fall within the genus of a nanobody that can bind to a target, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
The instant claims are directed to a class of nanobodies that include “a ‘vast’ number of molecules comprising an undefined structure (claims 1, 2, 5 and 7), and still be able to bind a generic target (claims 1, 2 and 8) or the spike protein of a SARS-CoV-2 or variant thereof, in view of teachings for the specification. It would be necessary to first generate and then screen each candidate antibody and fragments thereof, with the recited function to determine whether it met the functional limitations of “able to binds to a generic target or the spike protein of a SARS-CoV-2 or variant thereof”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the nanobody, they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
The specification does not reasonably provide enablement to make the invention of claims 1, 2, 5, 7 and 8 as it is currently written. The specification does reasonably provide enablement to make and use the invention of nanobody VHH72 and the target being a spike protein of SARS-CoV-2 as discussed above.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary, the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
In addition, any unspecific CDR sequences becoming a concern of whether a nanobody will bind to an epitope, which can happen when you recombine all these CDRs into different species is not predictable. This is evidenced by the fact that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff teaches that the alteration of a single amino acid in a single CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (entire article, Abstract).)
Moreover, claims not containing elements critical or essential to the practice of the invention, such as nanobodies not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate nanobody framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
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, 2, 5, 7 and 8 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 1, 2, 5, and 8 contains the trademark/trade name “nanobody”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a protein capable of binding to an epitope and, accordingly, the identification/description is indefinite.
Claim 1 recites, “a fluorogenic small molecule conjugate…around a target-binding domain of the nanobody”. However, the specification nor the claims provide an explanation of what the metes and bounds of “around a target-binding domain”. Therefore, it is unclear what this limitation includes and excludes and where “around a” specifically is relative to the claimed domain. Claims 5, 7 and 8 are also rejected since they depend from claim 1, but do not remedy this deficiency.
Claim 8 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of nanobodies is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the nanobodies claimed are structurally different from each other.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1 and 2 are rejected under 35 U.S.C. 102a1 as being anticipated by Zhang et al. (Cancer Cell Int, 2020, Vol 20, pages 1-16).
The claimed invention is drawn to a fluorogenic sensor comprising a nanobody and a fluorogenic small molecule conjugated at or around a target-binding domain of the nanobody, wherein the sensor is for detecting a target.
Applicant’s disclosure does not provide a definition for “around a target-binding domain of the nanobody”.
Zhang et al. teach an Anti-EGFR-Nanobody@PLGA-IR1048MZ-Cat (Nb@IC-NPs) nanobody complex was obtained based on the formation of disulfide bond between PLGA-SH (which comprises a fluorescent dye) and Anti-EGFR-Nanobody [see abstract]. The fluorescent dye, which meets the claimed requirement of a fluorogenic small molecule and the disulfide bonds locate the dye "around a target-binding domain of the nanobody”.
Therefore, Zhang et al. anticipate the instant invention.
Claim(s) 1, 5 and 7 are rejected under 35 U.S.C. 102a1 as being anticipated by Hanke et al. (Nature Communications, 2020, Vol 11, pages 1-9) as evidenced by Sigma-Aldrich product sheet (2018).
The claimed invention is drawn to a fluorogenic sensor comprising a nanobody and a fluorogenic small molecule conjugated around a target-binding domain of the nanobody, wherein the sensor is for detecting a target. The nanobody binds to a spike protein of a coronavirus, such as SARS-CoV-2 or a variant thereof. Applicant’s disclosure does not provide a definition for “around a target-binding domain of the nanobody”.
Hanke et al. teach the generation of a nanobody, Ty1, from alpaca that binds to the receptor binding domain of a SARS-CoV-2 spike glycoprotein. [see right column of page 2] Hanke et al. teach that the fluorophore AS635P is bound to Ty1 in the C-terminus [right column of page 3 and left column of page 7]. As evidenced by Sigma-Aldrich product sheet for 95408 Abberior STAR 635P, azide, AS635P has a molecular weight of 1254g/mol, which classifies it as a small molecule per applicant’s specification (see claim interpretation above). The fluorophore, which meets the claimed requirement of a fluorogenic small molecule and conjugation of the fluorophore to the nanobody meets the limitation of "around a target-binding domain of the nanobody”.
Therefore, Hanke et al. anticipate the instant invention.
Claim Rejections - 35 USC § 103
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, 2, 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Hanke et al. (supra) as evidenced by Sigma-Aldrich product sheet (2018) in view of Mills et al. (Chembiochem, 2009, Vol. 10, No. 13, pages 2162-2164).
The claimed invention is drawn to a fluorogenic sensor comprising a nanobody and a fluorogenic small molecule conjugated at a target-binding domain of the nanobody, wherein the sensor is for detecting a target. The nanobody binds to a spike protein of a coronavirus, such as SARS-CoV-2 or a variant thereof.
Hanke et al. teach the generation of a nanobody, Ty1, from alpaca that binds to the receptor binding domain of a SARS-CoV-2 spike glycoprotein. [see right column of page 2] Hanke et al. teach that the fluorophore AS635P is bound to Ty1 in the C-terminus [right column of page 3 and left column of page 7]. As evidenced by Sigma-Aldrich product sheet for 95408 Abberior STAR 635P, azide, AS635P has a molecular weight of 1254g/mol, which classifies it as a small molecule per applicant’s specification (see claim interpretation above). The fluorophore, which meets the claimed requirement of a fluorogenic small molecule and conjugation of the fluorophore to the nanobody meets the limitation of "around a target-binding domain of the nanobody”.
However, Hanke et al. do not teach that a nanobody possesses a fluorogenic small molecule conjugated at the target-binding domain of the nanobody.
Mills et al. teach the generation of a Fab fragment of antibody 5c8 that possesses a substitution of an isoleucine at position 98 in the light chain with a 7-hydroxycoumarin moiety. This moiety is a fluorescent amino acid and is therefore a small molecule in view of paragraphs 36 and 39 of the instant specification and working example 1 of the instant specification. Mills et al. teach that moiety is attached to the Fab in proximity to the binding domain, but does not directly contact the antigen (CD40L). [see 3rd paragraph on page 2] Mills et al. also teach that antibodies that are chemically modified with small molecule fluorophores near the combining site fluorescently signal the interaction of the antibody and its ligand. [see 2nd paragraph on page 1]
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Hanke et al. in order to attached a fluorogenic small molecule at the target-binding domain of the nanobody. One would have been motivated to do so, given the suggestion by Hanke et al. that a VHH specific for the spike protein of a SARS-CoV-2 virus can be constructed with a fluorophore site-specifically attached “around the target binding domain”. There would have been a reasonable expectation of success, given the knowledge that antibodies with a site-specific attachment of a fluorogenic small molecule to the target-binding domain can be generated in order to monitor binding of the target, as taught by Mills et al. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Hanke et al. (supra) as evidenced by Sigma-Aldrich product sheet (supra) in view of Mills et al. (supra) as applied to claims 1, 2, 5, and 7 above, and further in view of Wrapp et al. (Cell, 2020, Vol. 181, pages 1004-1015).
The claimed invention is drawn to a fluorogenic sensor comprising a nanobody and a fluorogenic small molecule conjugated at or around a target-binding domain of the nanobody, wherein the sensor is for detecting a target. The nanobody is VHH72 and the nanobody binds to a spike protein of a coronavirus, such as SARS-CoV-2 or a variant thereof.
Hanke et al. teach the generation of a nanobody, Ty1, from alpaca that binds to the receptor binding domain of a SARS-CoV-2 spike glycoprotein. [see right column of page 2] Hanke et al. teach that the fluorophore AS635P is bound to Ty1 in the C-terminus [right column of page 3 and left column of page 7]. As evidenced by Sigma-Aldrich product sheet for 95408 Abberior STAR 635P, azide, AS635P has a molecular weight of 1254g/mol, which classifies it as a small molecule per applicant’s specification (see claim interpretation above). The fluorophore, which meets the claimed requirement of a fluorogenic small molecule and conjugation of the fluorophore to the nanobody meets the limitation of "around a target-binding domain of the nanobody”.
However, Hanke et al. do not teach that a nanobody possesses a fluorogenic small molecule conjugated at the target-binding domain of the nanobody, wherein the nanobody is VHH72.
Mills et al. teach the generation of a Fab fragment of antibody 5c8 that possesses a substitution of an isoleucine at position 98 in the light chain with a 7-hydroxycoumarin moiety. This moiety is a fluorescent amino acid and is therefore a small molecule in view of paragraphs 36 and 39 of the instant specification and working example 1 of the instant specification. Mills et al. teach that moiety is attached to the Fab in proximity to the binding domain, but does not directly contact the antigen (CD40L). [see 3rd paragraph on page 2] Mills et al. also teach that antibodies that are chemically modified with small molecule fluorophores near the combining site fluorescently signal the interaction of the antibody and its ligand. [see 2nd paragraph on page 1]
Wrapp et al. teach the generation of VHH72 in Llamas and test its binding affinity for the spike protein of SARS-CoV-2. [see page 1005, right column and page 1008, left column and Figure 4]
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Hanke et al. in order to attached a fluorogenic small molecule at the target-binding domain of the nanobody, wherein the nanobody is VHH72. One would have been motivated to do so, given the suggestion by Hanke et al. that a VHH specific for the spike protein of a SARS-CoV-2 virus can be constructed with a fluorophore site-specifically attached “around the target binding domain”. There would have been a reasonable expectation of success, given the knowledge that antibodies with a site-specific attachment of a fluorogenic small molecule to the target-binding domain can be generated in order to monitor binding of the target, as taught by Mills et al., and also given the knowledge that VHH72 produced by Llamas and specific for SARS-CoV-2 spike protein has been previously produced and tested, as taught by Wrapp et al. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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.
Claims 1 and 2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 46 of copending Application No. 19116340 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the invention of the copending application is drawn to a species of the claimed genus of the instant invention. Claim 46 recites, “A fluorogenic sensor for detecting an EGFR protein comprising: a nanobody that binds an epidermal growth factor receptor (EGFR) protein; and a fluorogenic small molecule conjugated to a target-binding domain of the nanobody.”. Therefore, the copending application anticipates the instant invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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