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 II (claims 16-19 and 24) in the reply filed on 4/14/26 is acknowledged. The traversal is on the ground(s) that the shared technical feature alleged by the Office Action (i.e., a thermo-responsive microbead having a lanthanide spectral signature and a binding moiety immobilized to the microbead) is overly broad and does not capture significant features recited by the claims. Applicant asserts that the claims contribute over the art at least through the combination of a (1) a hydrogel microbead whose diameter can be precisely modulated by a temperature change across an LCST, and (2) lanthanide spectral encoding that allows each bead to serve as an identifier in an arrayed, high-throughput mechanotransduction assay. Applicant further argues that Hong does not disclose any polymeric bead whose diameter is modulated by crossing an LCST, nor does it describe embedding spectral codes in a bead, nor using such beads in multiplexed single-cell arrays with optical decoding. Applicant also argues that Lin does not disclose any application of mechanical force to cells using bead expansion or otherwise, nor does Lin describe single-cell microwell arrays, bead-cell pairing, or live-cell readouts such as calcium flux. The beads of Lin are not used in any cell mechanotransduction assay.
These arguments are not persuasive regarding the groups of inventions lacking the same or corresponding special technical features since the shared special technical features in common (see claims 1, 16 and 25 for comparison) are a thermo-responsive microbead having a lanthanide spectral signature and a binding moiety immobilized thereon, wherein the binding moiety targets a mechanosensitive molecule on the surface of a cell. These limitations are specifically taught by Lin in view of Hong.
Lin teaches that stimuli-responsive aqueous microgels undergo a change in volume in response to a change in the environment such as temperature. Page 20, second para.
Lin discloses the functionalization of lanthanide encoded microgels with biomolecules and use of these microgels as model cells in quantifying number of biomarkers that can be detected by mass spectrometry. See page 34, first para.
Lin also discloses that not only can different types of Ln ions be used to distinguish one set of particles from another, but different concentrations of the same Ln ion can also be used. This expands the capability and size of the multiplexted assay. See page 5, first para. [See also page 29 regarding lanthanides.]
Lin further discloses that lanthanide-encoded beads and a lanthanide containing reporter. In the assay, each type of lanthanide-encoded bead is precoated with a specific type of bioaffinity agent (e.g., an antibody). The antibodies in the bead capture their target analytes (e.g., a protein or antigen). After washing the analyte-coated beads, an analyte-specific detecting agent (e.g., a primary antibody) was incubated with the beads, during which the analyte-specific detecting agent binds to the target analytes. After removal of excess detecting agents from the beads, a given secondary antibody that can be used to target all the detecting primary antibodies is used as a common reporter. See page 6, second para.
Lin discloses that Ln metals loaded into particles serve as classifier ions, which encode the beads. See Page 20, first para.
Moreover, while Lin teaches that the lanthanide-encoded bead is precoated with a specific type of bioaffinity agent, Lin is silent as to the agent being a binding moiety that targets a mechanosensitive molecule on the surface of a cell.
However, Hong discloses that it is known that TCR-peptide-bound MHC interactions predict responses of CD8+ T cells (see abstract) and are useful in assays for yielding insights to T cell biology (see page 3557, right column).
It would have been obvious to one skilled in the art to provide TCR-peptide-bound MHC as the binding moiety on the Lin invention as such binding moiety is known in the art to be used for studying T cells, as shown by Hong.
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 16-19 and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 16 recites:
“A thermo-responsive microbead having a lanthanide spectral signature and a binding moiety immobilized to the microbead, wherein the binding moiety targets a mechanosensitive molecule on the surface of a cell and the microbead comprises a thermo-responsive polymer having a phase transition temperature in the range of about 25 °C to about 45 °C.” Emphasis added.
It is not clear what part of the claim is a preamble and what part of the claim is the body of the
claim which recites required limitations. For examination purposes, all the recited limitations are considered required, however, clarification is required to overcome this rejection.
The remaining claims are rejected since they depend from claim 16 without clarifying the above.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 16-19 and 24 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 claims contain 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 pre-AIA the inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims require a binding moiety immobilized to the microbead, wherein the binding moiety targets a mechanosensitive molecule on the surface of a cell (see claim 16, lines 2-3).
The specification does not describe which amino acid residues, nucleic acid residues or other molecular components are responsible for the functions claimed. Rather, these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides a few examples of potential generic agents [para. 0034 of Applicant’s specification in the Pre-Grant Publication US 20230384308], it fails to disclose the structures common to all members of the genus of peptides encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant agents and fails to disclose which regions of the agents are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of agents (binding moiety that targets a mechanosensitive molecule on the surface of a cell), i.e. the required starting materials for the claims, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of binding agents nor guidance as to which of the myriad of molecules encompassed by the binding agents would meet the limitations of the claims.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must 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.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of the genus of binding agents, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
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.
Claim(s) 16-19 and 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lin (“Lanthanide-Containing Microgels intended for Bead-Basd Bioassays by Mass Cytometry”, Online available at: https://tspace.library.utoronto.ca/bitstream/1807/68898/1/Lin_Wanjuan_201311_PhD_thesis.pd., November 1, 2013, pages 1-272) (cited of record and in IDS of 5/22/23)
in view of Hong (Force-Regulated in Situe TCR-Peptide-Bound MHC Class II Kinetics Determine Functions of CD4+ T Cells”, The Journal of Immunology, Vol. 195, No. 8, Sept 2015, pp.3557-3564) (cited of record and in IDS of 5/22/23)
and further in view of Ohnishi (US 20080199884).
Claim 16 recites:
“A thermo-responsive microbead having a lanthanide spectral signature and a binding moiety immobilized to the microbead, wherein the binding moiety targets a mechanosensitive molecule on the surface of a cell and the microbead comprises a thermo-responsive polymer having a phase transition temperature in the range of about 25 °C to about 45 °C.” Emphasis added.
Lin teaches that stimuli-responsive aqueous microgels undergo a change in volume in response to a change in the environment such as temperature. Page 20, second para.
Lin discloses the functionalization of lanthanide encoded microgels with biomolecules and use of these microgels as model cells in quantifying number of biomarkers that can be detected by mass spectrometry. See page 34, first para.
Lin also discloses that not only can different types of Ln ions be used to distinguish one set of particles from another, but different concentrations of the same Ln ion can also be used. This expands the capability and size of the multiplexted assay. See page 5, first para. [See also page 29 regarding lanthanides.]
Lin further discloses that lanthanide-encoded beads and a lanthanide containing reporter. In the assay, each type of lanthanide-encoded bead is precoated with a specific type of bioaffinity agent (e.g., an antibody). The antibodies in the bead capture their target analytes (e.g., a protein or antigen). After washing the analyte-coated beads, an analyte-specific detecting agent (e.g., a primary antibody) was incubated with the beads, during which the analyte-specific detecting agent binds to the target analytes. After removal of excess detecting agents from the beads, a given secondary antibody that can be used to target all the detecting primary antibodies is used as a common reporter. See page 6, second para.
Lin discloses that Ln metals loaded into particles serve as classifier ions, which encode the beads. See Page 20, first para.
Moreover, while Lin teaches that the lanthanide-encoded bead is precoated with a specific type of bioaffinity agent, Lin is silent as to the agent being a binding moiety that targets a mechanosensitive molecule on the surface of a cell.
However, Hong discloses that it is known that TCR-peptide-bound MHC interactions predict responses of CD8+ T cells (see abstract) and are useful in assays for yielding insights to T cell biology (see page 3557, right column).
It would have been obvious to one skilled in the art to provide TCR-peptide-bound MHC as the binding moiety on the Lin invention as such binding moiety is known in the art to be used for studying T cells, as shown by Hong.
Also, Lin is silent as to the thermo-responsive polymer having a phase transition temperature in the range of about 25 °C to about 45 °C. Examiner notes that Lin discloses use of poly(NIPAm/MAA/PEGMA) with varying MAA content as the microgel (see page 44, last partial para.). Examiner notes that it is not clear if the disclosed microgel has a phase transition temperature in the range of about 25 °C to about 45 °C.
Applicant’s disclosure, as well as Applicant’s claim 17, show that poly(N-isopropylacrylamide) has a phase transition temperature in the range of about 25 °C to about 45 °C.
Ohnishi discloses that poly(N-isopropylacrylamide) is a known heat responsive polymer and is suitable for use in forming beads for performing assays. Ohnishi also discloses the phase transition temperature of poly(N-isopropylacrylamide) is 32.degree. C.
Specifically, Ohnishi discloses the following.
Particularly, in the magnetic nanoparticles having, immobilized thereto, the stimuli-responsive polymers described in FIG. 1B, since the aggregate is formed depending on change in temperature or pH, it is easy to recover the dispersed magnetic fine particles [such as by a magnet]. Para. 0050.
Disclosed is a binding method comprising providing the nanoparticles having immobilized thereon an antibody against oocyst as the target. Para. 0051.
When magnetic nanoparticles having, immobilized thereto, stimuli-responsive polymers containing a binding factor bound thereto are used as magnetic nanoparticles, the oocysttimuli-responsive polymer immobilized magnetic nanoparticle complex is easily aggregated by imparting the corresponding stimulation, so that recovery of the complex is facilitated. Para. 0053.
The stimuli-responsive polymer means a polymer having a property of precipitating and aggregating the polymer in a solvent containing the polymer in response to stimulation such as temperature, pH, light, magnetic field, or electricity. When the above stimuli-responsive polymer is immobilized to the magnetic nanoparticle, after oocyst and immunological magnetic nanoparticle form an immunocomplex, the immunocomplex is aggregated by imparting stimulation to the solvent containing the immunocomplex, so that it can be easily magnetically separated (recovered). Any of the conventionally known stimuli-responsive polymers can be used. Para. 0064.
In the invention, as preferred stimuli-responsive polymers, there may be, for example, mentioned a pH responsive polymer wherein a physical property (solubility toward a solvent, a form, or the like) responds to change in pH, a light responsive polymer wherein a physical property responds to change in wavelength of light, and a heat responsive polymer wherein a physical property responds to change in temperature. Particularly preferred is a heat responsive polymer. The heat responsive polymer means a polymer which reversibly repeats aggregation and dissolution in an aqueous solution upon temperature change. As the heat responsive polymer, there are known a polymer having lower critical solution temperature (LCST) and a polymer having upper critical solution temperature (UCST). Specifically, poly-N-isopropylacrylamide is known as a polymer exhibiting LCST in an aqueous solution and its phase transition temperature is 32.degree. C. A copolymer of acrylamide and N-acetylacrylamide or the like is known as a polymer exhibiting UCST in an aqueous solution and its phase transition temperature can be varied depending on the ratios of individual monomer components. Para. 0065.
Thus, Ohnishi discloses that poly(N-isopropylacrylamide) is a known heat responsive polymer and is suitable for use in forming beads for performing assays. Ohnishi also discloses the phase transition temperature of poly(N-isopropylacrylamide) is 32.degree. C. While Ohnishi teaches use of a heat responsive polymer in a magnetic nanoparticle to precipitate and aggregate the polymer to facilitate recovery (via magnetic nanoparticle), Ohnishi nevertheless shows that poly(N-isopropylacrylamide is a known heat responsive polymer, and thus its use in the modified Lin invention would have been obvious to the skilled artisan as a substitute for the stimuli-responsive (heat-responsive) microgel of Lin. Moreover, Ohnishi teaches that such nanoparticles have the advantage of precipitating and aggregating the polymer in an aqueous solution upon imparting the stimulation [heat], after the binding reaction, which facilitates recovery (para. 0064).
As to Applicant’s claim 17, the poly(N-isopropylacrylamide) is taught by Ohnishi (see discussion above).
As to claim 18, the binding moiety targets a T-cell receptor (see discussion of Lin above regarding claim 16).
As to claim 19, the binding moiety being a peptide-loaded MHC complex, wherein the peptide comprises a candidate T-cell, is discussed above (see discussion of Hong above regarding claim 16).
As to claim 24, Lin discloses teaches and suggests multi-well microtiter plates for increased throughput in biomarker detection (page 3 under section “1.1.2 Bead-Based Assays”).
Conclusion
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/Ann Montgomery/Primary Examiner, Art Unit 1678
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