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 1-15 are pending and under examination on the merits.
Priority
This application is a 371 of PCT/NL2021/050637, filed 10/20/2021, which claims benefit of priority to Netherlands Application No. 2026714, filed 10/20/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
IDS
The information disclosure statement (IDS) filed 04/19/2023 has been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code (see for example, page 25 of the instant specification). See MPEP § 608.01.
Claim Objections
Claim 8 is objected to because of the following informalities: the recitation that “the cells of the first type and or the cells of the second type are human,” should read “the cells of the first type and/or the cells of the second type are human,”. Appropriate correction is required.
Claim Interpretation
In claim 8, the limitation that “the cells of the first type and or the cells of the second type are human,” is being interpreted such that “and or” is being read as “and/or”.
Limitations modified (preceded) by the term ‘preferably’ are not being interpreted as required by the claim(s).
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 1-15 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.
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.
The Application claims a broad genus of LFA-1 antagonists, including small molecules and antibodies binding LFA-1 or binding ICAM-1, where the claims are drafted broadly enough to encompass aptamers or any other class of antagonistic molecule (see the disclosure in its entirety and exemplary lines 20-22 of page 23 of the instant specification) while only describing concretely a small number of antagonists known in the art (where only 1; BIRT377 is actually demonstrated to function in the method as claimed) species of LFA-1 antagonists (see for example, page 25 of the instant specification) Regarding antibody antagonists of LFA-1, the genus not only encompasses two different targets to be bounds, but further impermissibly allows for variation within the CDRs without disclosure of a conserved structure/representative number of species to adequately describe said genus of antibody antagonists. The Application discloses that certain LFA-1 antagonists are known in the art (see for example, page 25 of the instant specification), but does not provide evidence that all of these species or their structural/functional equivalents would function in the method(s) instantly claimed. Therefore, in view of this disclosure, Applicant is claiming a broad genus of antibodies without a representative number of species of said genus. The specification does not provide adequate written description for the entire claimed genus of species of antibodies or of CDRs binding LFA-1 or ICAM-1 for use in the method(s)as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequence might be included in the genus.
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 only fully disclosed that certain antibodies binding LFA-1 and ICAM-1 are known in the art for consideration. Thus, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of only 1 non-antibody species demonstrated to function in the claimed method combined with the art teaching that antibodies binding LFA-1 or ICAM-1 are generally known in the art is not sufficiently representative to describe the entire genus of antibody LFA-1 antagonists claimed (encompassing CDRs not described or even invented).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences that confer upon an antibody the ability to function as claimed because the instant specification does not provide structural antibody features that correlate with capacity to function as claimed.
Absent a clear description of the at least minimal structural features correlating with a functional ability to function as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be mutated/varied/interchanged such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al. (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, a mutation in the CDRs may result in a paratope unable to antagonize LFA-1. Rabia, et al. (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al. report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus comprising the claimed CDR sequences may be combined/mutated such that the resultant antibody possesses an antigen-binding site capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations, that correlate with the ability to function as claimed, and because the generic number of disclosed species discussed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
The claims require an antibody capable of antagonizing LFA-1. The specification does not describe which amino acid residues of the antibody are responsible for the functions claimed. Rather, the specification implies that 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 disclosure of a few antibodies generically known in the art, it fails to disclose the structures common to all members of the genus of antibodies encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant antibodies and fails to disclose which sequences 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 antibodies that would function in the method(s) as claimed, 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.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Although screening techniques can be used to isolate CDR variant antibodies 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.”
Likewise, non-antibody LFA-1 antagonists are insufficiently described. The species disclosed by the instant Application, as discussed above, are insufficient in number to convey a representative number of species and no structure is disclosed as required for or corresponding to a capacity to antagonize LFA-1 in the method as claimed. Protein modification and biochemistry is a field marked by unpredictability.
Regarding the state of the art, Listov et al (Opportunities and challenges in design and optimization of protein function. Nat Rev Mol Cell Biol 25, 639–653 (2024)) teach that the primary amino acid sequence determines downstream structure (protein folding), which then determines function (presenting both the inverse folding problem and the inverse function problem (see for example, Figure 1 and its caption; see also Mishra et al (Inaccurate secondary structure predictions often indicate protein fold switching. Protein Sci. 2019 Aug;28(8):1487-1493. doi: 10.1002/pro.3664. Epub 2019 Jun 17)). Expanding on these problems in proteomics, Reardon (Nature 635, 246-248 (2024)) explains that the goal of designing a protein with known and predictable function, binding partners, size, location, and other traits is, for the moment, a dream. Reardon teaches that further challenges in protein design include predicting how a protein, even if it binds to target, will function upon said binding. Reardon teaches that the primary structure (amino acid sequence) of a protein is critical to function, noting that even proteins of similar shape do not execute the same functions, while those with different shapes may carry out the same tasks. Reardon goes on to teach that it is not always apparent which parts of the primary sequence are important; a seemingly useless amino-acid chain on the side of an enzyme, for instance, might affect how tightly a protein can bind to other molecules or its ability to flip between conformational states. Moreover, Reardon explains that when researchers attempt to solve the structure of a protein experimentally, they often end up seeing only the most stable conformation, which is not necessarily the form the protein takes when it is active (see for example, pages 246-247 of Reardon).
Therefore, the genera of claimed LFA-1 antagonists are insufficiently described through a demonstrated correlation of a conserved/identifying structure with the claimed function(s) or through a representative number of species.
Therefore, the antibodies, as claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s). Therefore, claims 1-15 are deemed to fail to meet the written description requirement, as presently drafted.
35 USC § 112(b)
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 4, 10, 12, and 14 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 4, 10, 12, and 14 are indefinite in scope because it is unclear whether the limitation(s) modified (following after) the term ‘preferably’ are required by the claim or merely reflect improper recitations of a preference (which are not required by the claim and which would be more appropriately presented in the specification) (see MPEP § 2173.05(d)).
35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4, in reciting all possible options for when the first, second, or first and second cell type(s) are incubated with the LFA-1 antagonist fails to further limit the recited scope of claim 1 from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, and 5-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hosseini et al (Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17852-7. doi: 10.1073/pnas.0905384106; citation 2 under Nonpatent Literature section of the 04/19/2023 IDS; see also the Hosseini et al correction published 2010 noting the lack of an NIH funding acknowledgment (Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2373. doi: 10.1073/pnas.0914350107. Epub 2010 Jan 19. Erratum for: Proc Natl Acad Sci U S A. 106:17852. PMCID: PMC2836702)).
Regarding claim 1, Hosseini et al teach that during adaptive immune responses, T lymphocytes (T cells) recognize antigenic peptides presented by MHC molecules on antigen-presenting cells (APCs). This recognition results in the formation of a so-called immune synapse (IS) at the T-cell/APC interface, which is crucial for T-cell activation. Dynamic analysis of T-cell/APC interaction was accomplished by atomic force microscopy (AFM) and correlated with the kinetics of synapse formation that also reached a maximum as determined by high-throughput multispectral imaging flow cytometry. Because the integrin lymphocyte function antigen-1 (LFA-1) and its counterpart intercellular adhesion molecule-1 (ICAM-1) are prominent members of a mature IS, the effect of a small molecular inhibitor for LFA-1, BIRT377, was investigated. BIRT377 almost completely abolished the interaction forces, emphasizing the importance of LFA-1/ICAM-1-interactions for firm T-cell/ APC adhesion (see for example, the abstract at page 17852). Formation of an IS includes the coordinated translocation of several protein complexes, among others TCR and its ligand pMHC, and the integrin lymphocyte function-associated antigen-1 (LFA-1) and its counterpart intercellular adhesion molecule 1 (ICAM-1). Subsequent motor protein motion yields a cytoskeleton contraction, which exerts low forces on LFA-1 to induce occupied integrin activation and to fully arrest the two cells for adhesion. This force has to be counterbalanced on the APC side, resulting in a high interaction force between T cells and APCs. A well-studied T-cell/APC pair was selected, namely the 3B11 T hybridoma and the LK35.2 B cell line (a lymphocyte presenting an antigen/peptide at its MHC serving as an APC) because in orientating experiments 3B11 cells (T cells) could be attached well via antibodies to the cantilever of the AFM instrument. The 3B11 T hybridoma recognizes a peptide HEL35–45 derived from the model antigen hen egg lysozyme presented by Ak MHC class II positive APC (see for example, pages 17852-17853). 3B11 cells were labeled with the green dye CFSE and LK35.2 B cells were labeled with the red dye SNARF. Cells were mixed at a 1:1 ratio, centrifuged briefly, and incubated for various times before fixation with paraformaldehyde. Conjugates were identified by FACS analysis by virtue of simultaneous green and red signals. Hosseini et al analyzed whether the small molecule antagonist BIRT377, which inhibits the high-affinity state of LFA-1, would interfere with conjugate formation. Fig. 1B shows that BIRT377 blocked conjugate formation effectively. Conjugates formed also in the absence of peptide, albeit to a lower degree, and these conjugates were also blocked by BIRT377 (see for example, page 17853). Note that the phrasing that BIRT377 blocked conjugate formation (see for example, page 17853) would support that BIRT377 as contacted before and/or during conjugate formation. The cantilever attached T cell was moved near a B cell to allow for conjugate formation using forces of 1-2nN pressing the cells together, cells were then separating by retraction of the cantilever (application of force on the second cell in a direction away from the first cell) which is deemed to read upon the limitation of claim 1, step (c) (see for example, column 1 of page 17854).
Regarding claim 3, Hosseini et al teach incubation for complex formation at various time ranging from 0 min-60 min (see for example pages 17853-17854 and Figure 2B-C).
Regarding claim 5, Hosseini et al teach kinetics of conjugate formation in the presence of LFA-1 were observed in an incubation window of 0-60 min (see for example, Figure 1 and its caption at page 17853 and figure 2 and its caption at page 17854).
Regarding claim 6, Hosseini et al teach that the LFA-1 antagonist is BIRT377.
Regarding claim 7, as discussed above, Hosseini et al teach the use of a T cell as the lymphocyte for use in the method.
Claims 1, 3, and 5-7 are deemed anticipated by Hosseini et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 -7 and 9-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hosseini et al, as applied to claims 1, 3, and 5-7 above, in view of Candelli et al (WO2018083193A2; citation 1 under Foreign Patent Documents on the 04/19/2023 IDS).
Regarding claim 1, as discussed above, Hosseini et al teach a method reading upon the limitations of instant claims 1, 3, and 5-7 where the applied force is mechanical (retraction of the cantilever) (see for example line 29 of page 11 through line 6 of page 12 of the instant specification which disclose known means in the art for studying cell-to-cell interaction include atomic force microscopy and acoustic force microscopy).
However, Hosseini et al do not teach that the embodiment where the force is an acoustic force on the cells of the second type in a direction away from the cells of the first type (see for example, pages 4-9 and 31 of the instant specification).
However, Candelli et al teach a method of manipulating and/or investigating cellular bodies, comprising the steps of providing a sample comprising one or more cellular bodies in a fluid medium to be placed in a holding space with a functionalized wall surface (where the functionalized wall surface may comprise cells; see for example, lines 20-30 of page 8 of Candelli et al) to be contacted by the sample, wherein the sample is in contact with the functionalized wall surface portion (allowing for conjugate formation) during at least part of the step of application of the acoustic wave, wherein the method comprises generating an acoustic wave in the holding space exerting a force on the one or more cellular bodies of the sample in the holding space in a direction away from the functionalized wall surface portion (see for example, claim 1 of Candelli et al).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Hosseini et al and Candelli et al. The artisan would have been motivated to make and use the invention as claimed because both references teach methods for investigating cell-binding/adhesion forces where the artisan would have understood that the atomic force microscopy of Hosseini et al and the acoustic force microscopy of Candelli et al are equivalent means for investigating cell binding/adhesion forces between 2 cells such as the B and T cell pair of Hosseini et al where the artisan would have been motivated to investigate the role of LFA-ICAM-1 interaction in B cell-T cell interaction where LFA-1 inhibition using BIRT377 would further allow for investigation of TCR-antigen binding force without the contributing/confounding force of LFA-1/ICAM-1 interaction. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 2, Candelli et al teach that the method comprises generating an acoustic wave in the holding space exerting a force on the one or more cellular bodies of the sample in the holding space in a direction away from the functionalized wall surface portion (see for example, claim 1 of Candelli et al).
The artisan would have found it obvious, with a reasonable expectation of success, to modify the method of Hosseini et al to comprise the use of the acoustic force microscopy of Candelli et al for the reasons that the combination of references is made obvious as discussed above.
Regarding claim 3, Hosseini et al teach incubation for complex formation at various time periods ranging from 0 min-60 min (see for example pages 17853-17854 and Figure 2B-C). Additionally Candelli et al teach incubation of T-cell engineered to express a TCR against an antigen presented on a tumor cell line where tissue expressing said tumor cell line were functionalized to the wall of the sample holder with incubation of the T cells with the functionalized wall for 30 minutes prior to application of acoustic force allowing for sorting of T cells based on avidity (see for example, line 20 of page 30 through line 11 of page 33).
The artisan would have found it obvious, with a reasonable expectation of success, to modify the method of Hosseini et al to comprise the use of the acoustic force microscopy of Candelli et al with an incubation time of 0-60 min for the reasons that the combination of references is made obvious as discussed above.
Regarding claim 4, it is noted that alternative times T1, T2, T3, and T4 are never disclosed as being in or being compatible for interpretation as sequential steps in a single method where T1 is chronologically before and proceeded by T2, which is chronologically before and proceeded by T3, which is chronologically before and proceeded by T4. Instead, throughout the disclosure, the time points noted as T1-T4 appear to be discreet and part of separate methods such that any one of alternatives i)-iv) of claim 4 may be independently met. This is further supported by the connection of the alternative using an ‘or’ transition term. Moreover, the drafting alternatives i)-ii) does not preclude a scenario where both cell types are independently contacted with BIRT377 (LFA-1 antagonist) prior to contacting the two cell types together. Accordingly, Hosseini et al teach cells were incubated and fixed and that BIRT377 blocked conjugate formation (cell binding) (see for example, column 1 of page 17853). This would suggest that at least 1 of the options recited in instant claim 4 at alternatives i)-iv) is met by the teachings of Hosseini et al. The individual options are merely time points obvious to the artisan to try for incubating with the LFA-1 antagonist as there are a finite number of options of time periods for incubating the cells with LFA-1 antagonist (all of which are accounted for in the recited options of i-iv of claim 4).
The MPEP provides that:
“The Supreme Court in KSR reaffirmed the familiar framework for determining obviousness as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), but stated that the Federal Circuit had erred by applying the teaching-suggestion-motivation (TSM) test in an overly rigid and formalistic way. KSR, 550 U.S. at 404, 82 USPQ2d at 1391. Specifically, the Supreme Court stated that the Federal Circuit had erred in four ways: (1) “by holding that courts and patent examiners should look only to the problem the patentee was trying to solve ” (Id. at 420, 82 USPQ2d at 1397); (2) by assuming “that a person of ordinary skill attempting to solve a problem will be led only to those elements of prior art designed to solve the same problem” (Id.); (3) by concluding “that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘obvious to try’” (Id. at 421, USPQ2d at 1397); and (4) by overemphasizing “the risk of courts and patent examiners falling prey to hindsight bias” and as a result applying “[r]igid preventative rules that deny factfinders recourse to common sense” (Id.). See also Novartis Pharms. Corp. v. West-Ward Pharms. Int'l Ltd., 923 F.3d 1051, 1059, 2019 USPQ2d 171676 (Fed. Cir. 2019); Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034, 1047-48, 120 USPQ2d 1400, 1410 (Fed. Cir. 2016); and Aventis Pharma S.A. v. Hospira, Inc., 675 F.3d 1324, 1332, 102 USPQ2d 1445, 1449 (Fed. Cir. 2012)… Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” Id. (2) “In Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., . . . [t]he two [pre-existing elements] in combination did no more than they would in separate, sequential operation.” Id. at 416-17, 82 USPQ2d at 1395. (3) “[I]n Sakraida v. AG Pro, Inc., the Court derived . . . the conclusion that when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” Id. at 417, 82 USPQ2d at 1395-96 (Internal quotations omitted.). The principles underlining these cases are instructive when the question is whether a patent application claiming the combination of elements of prior art would have been obvious. The Supreme Court further stated that:
When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions.” Id,”
(see MPEP §2141(I)).
The recited alternative time points in the process for incubation with the LFA-1 antagonist would have been prima facie to obvious to the artisan. Precedent for said obviousness may be observed in Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.) (see MPEP 2144.04 IV).
The artisan would have found it obvious, with a reasonable expectation of success, to modify the method of Hosseini et al according to Candelli et al, where any of the instantly recited time points for LFA-1 antagonist incubation would have been obvious for the reasons articulated above.
Regarding claim 5, Hosseini et al teach that the peak number of mature IS was formed after approximately 30 min (see for example, column 2 of page 17853) and that kinetics of conjugate formation in the presence of LFA-1 was observed in an incubation window of 0-60 min (see for example, figure 1 and its caption at page 17853 and figure 2 and its caption at page 17854).
The artisan would have found it obvious, with a reasonable expectation of success, to modify the method of Hosseini et al to according to Candelli et al, where any of the instantly recited time points for LFA-1 antagonist incubation for an incubation period of 0-60 min would have been obvious for the reasons articulated above.
Regarding claim 6, Hosseini et al teach that the LFA-1 antagonist is BIRT377 (see for example, the abstract at column 1 of page 17852). Note that the alternatives of an LFA-1 binding antibody and an ICAM-1 binding antibody would have been obvious to the artisan as functional equivalents.
It is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to examine cell-cell binding/adhesion without the influence of LFA-1/ICAM-1 interaction (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have found it obvious, with a reasonable expectation of success, to modify the method of Hosseini et al and Candelli et al to use any art-known agent to inhibit/reduce LFA-1/ICAM-1 interaction as taught by Hosseini et al.
Regarding claim 7, as discussed above, Hosseini et al teach the use of a T cell and B cell in their method, rending the use of at least a T cell as the lymphocyte (which will bind the target cell expressing the antigen; see for example, pages 17852-17853) obvious and predictable with a reasonable expectation of success.
Regarding claims 9-10, Hosseini et al teach that the T cell (second cell type/lymphocyte) is attached to the cantilever and the B cell (first cell type; target cell expressing antigen) is immobilized on the bottom of a petri dish (see for example, see for example, column 1 of page 17854 and figure 3 and its caption at page 17855). Note that a carrier is defined in the instant specification “not in any particular way limited and may be of any suitable material, including for example glass, plastics, matrices (e.g. extracellular matrices such as Matrigel), polymers and that are suitable and/or regularly used in the field for the attachment of cells thereto” (see for example page 14 at lines 20-30). Note that Candelli et al discuss the use of a sample holder where cells may be functionalized to a wall of the sample holder to be contacted with sample (see for example, lines 20-30 of page 8 of Candelli et al).
The artisan would have found it obvious, with a reasonable expectation of success, to practice the method of Hosseini et al and Candelli et al for the reasons discussed above, where functionalizing the B cells of Hosseini et al onto the wall of the sample holder of Candelli et al for contact with a sample comprising the T lymphocytes of Hosseini et al for acoustic force microscopy according to Candelli et al would have been obvious to the artisan for investigation of cell binding/adhesion and avidity sorting where strong/specific binding is desired and to determine the binding strength without the effect of LFA-1/ICAM-1 interaction.
Regarding claim 11, Hosseini et al teach cells were incubated and fixed and that BIRT377 blocked conjugate formation (cell binding between the T cell and B cell pair) (see for example, column 1 of page 17853). Separate incubation of one or more of the cell types (B or T cells) with BIRT377 (the LFA-1 antagonist compound suspected to modulate binding of the first and second cell types) is not discussed in Hosseini et al. Moreover, where the goal is to examine the role of BIRT377 on first and second cell binding, the artisan would have found it obvious to incubate the two cell types in the presence of BIRT377. However, the claimed variations in incubation would have been obvious to try from a finite set of alternatives (cell type one prior to contact with cell type two, cell type two prior to contact with cell type 1, concurrent contacting of the two cell types and the LFA-1 antagonist, of contacting the bounds cell types 1 and two with the LFA1 antagonist (see MPEP §2141(I)).
Claim 11 is made obvious for the same reasons that claim 4 is made obvious, as discussed above.
Regarding claim 12, Hosseini et al teach that interaction forces are measured using deflection of a laser beam (optical) and atomic force microscopy (see for example, Figure 3 and its caption at page 17855). This is deemed to make obvious the third instantly recited option/alternative. Candelli et al similarly teach that detection of the cell body adhesion to the functionalized wall (which may comprise one or more cells) may be detected by optical or acoustic detection (see for example, lines 14-26 of page 9). Further, Candelli et al additionally teach screening of high-avidity T cell (lymphocytes) comprising collection of unbound T cells and collection of subsequently detached T cells after application of increasingly strong acoustic force (where cells displaced after stronger applied force would have higher avidity/stronger binding than unbound cells or cells detached after application of weaker acoustic force (see for example, page 32 of Candelli et al).
The artisan would have found it obvious, with a reasonable expectation of success, to practice the method of Hosseini et al and Candelli et al in order to screen for high avidity lymphocytes as taught by Candelli et al (see for example, pages 32-33). The artisan would have had a reasonable expectation of success in light of the combined disclosures of these prior art references.
Regarding claim 13, Candelli et al teach the use of acoustic force microscopy such that the force applied between the immobilized/functionalized cell and the sample cell is an acoustic wave (see for example, the abstract, pages 1-2 and 30-33).
Modification of the method of Hosseini et al to comprise acoustic force application and microscopy as taught by Candelli et al would have been obvious with a reasonable expectation of success to the artisan for the reasons iterated above.
Regarding claim 14, Candelli et al teach the use of acoustic wave to screen for T cells with high avidity to a melanoma patient-derived tumor cell line where the acoustic wave increases in force over time (to allow for T cells detached from the immobilized/functionalized adhered/immobilized/functionalized tumor cells by increasingly strong acoustic force (where cells requiring a strong acoustic force for detachment have higher avidity for the tumor cells) (see for example, the abstract, pages 1-2 and 30-33).
It would have been prima facie obvious to the artisan to modify of the method of Hosseini et al to comprise acoustic force application which increases in strength over time and microscopy as taught by Candelli et al with a reasonable expectation of success for reasons iterated above.
Regarding claim 15, Candelli et al teach that the force may be intermittently applied for intervals of 1-2 seconds or longer (see for example, pages 29-33, paying particular attention to the paragraph bridging pages 29-30) and the figures at pages 1/7-7/7).
It would have been prima facie obvious to the artisan to modify of the method of Hosseini et al to comprise acoustic force application periods of 1-2 seconds or longer with a reasonable expectation of success to the artisan for reasons iterated above.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hosseini et al in view of Candelli et al as applied to claims 1 -7 and 9-15 above, in further view of Moy et al (Exp Biol Med (Maywood). 2006 Sep;231(8):1306-12. doi: 10.1177/153537020623100804).
Regarding claim 8, Hosseini et al, either alone or in combination with Candelli et al, teach the limitations of claim 1. Hosseini et al briefly discuss the work of Moy et al involving human umbilical vein endothelial cells (HUVECs) (see for example, column 1 of page 17856). Candelli et al teach that the cellular bodies (presumably in the sample) may be cell portions of unicellular or multicellular groups such as human embryo (see for example, page 3 of Candelli et al)[note that a patient is never defined as human such that the recited use of melanoma patient-derived tumor cells is not deemed to explicitly teach that the cells are human).
Hosseini et al and Candelli et al do not explicitly state that the first or second cell type may be human.
However, Moy et al teach the application of atomic force microscopy to characterize the interaction between Individual pairs of living T lymphocytes (i.e., Jurkat cells) and human umbilical vein endothelial cells (HUVECs). The detachment of individual cell-cell conjugates was a complex process Involving several step-like rupture events and the viscoelastic deformation of cells on the scale of several microns. Adhesion between Jurkat cells and activated endothelial cells Increased with compression force and contact time, with the most dramatic changes occurring within the first half second of contact. After 0.25 sec of contact, E-selectin, ICAM-1, and VCAM-1 contributed to 18%, 39%, and 41% of total adhesion strength, respectively, suggesting that ICAM-1 and VCAM-1 contributed more than the selectins in supporting cell attachment (see for example, the abstract at page 1306 column 1).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because all three references pertain to the use of force microscopy to study cell-to-cell binding/adhesion/avidity where all three references discuss human cells and would, taken together, suggest to the artisan a reasonable expectation of success using human cells as the first, second, or both cell types to better understand the binding/adhesion/avidity in human cells. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
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 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-6 and 17-19 of U.S. Patent No. 11207684 B2 (reference A);
claims 1-2, 6, 9, and 12-15 of copending Application No. 18/725,403 (reference B);
claims 1, 10-11, and 13of copending Application No. 18/725,340 (reference C);
claims 1, 4 of copending Application No. 18/725,439 (reference D);
claims 1-2 of copending Application No. 18/863,923 (reference E);
claims 1, 5, 7 of copending Application No. 18/023, 273 (reference F);
claims 1, 4, and 19 of US Patent 11207684B2 (reference G);
claims 1-3 of US Patent 12403474B2 (reference H); and/or
claims 1-15 of US Patent 12053778B2 (reference I)
in view of Hosseini et al (correction published 2010 noting the lack of an NIH funding acknowledgment (Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2373. doi: 10.1073/pnas.0914350107. Epub 2010 Jan 19. Erratum for: Proc Natl Acad Sci U S A. 106:17852. PMCID: PMC2836702)), Candelli et al (WO2018083193A2; citation 1 under Foreign Patent Documents on the 04/19/2023 IDS), and Moy et al (Exp Biol Med (Maywood). 2006 Sep;231(8):1306-12. doi: 10.1177/153537020623100804).
Regarding claims 1-15, the above enumerated claims of references A-I are directed to a method for studying cell binding/interaction/adhesion/avidity between a sample cell type(s) and a cell immobilized/functionalized on the wall surface of a sample holder where a force is applied.
The above enumerated claims of references A-I do not claim the use of an LFA-1 antagonist or the use of human cells,
However, this is obvious in view of Hosseini et al, Candelli et al, and Moy et al, as discussed below.
Hosseini et al teach that during adaptive immune responses, T lymphocytes (T cells) recognize antigenic peptides presented by MHC molecules on antigen-presenting cells (APCs). This recognition results in the formation of a so-called immune synapse (IS) at the T-cell/APC interface, which is crucial for T-cell activation. Dynamic analysis of T-cell/APC interaction was accomplished by atomic force microscopy (AFM) and correlated with the kinetics of synapse formation that also reached a maximum as determined by high-throughput multispectral imaging flow cytometry. Because the integrin lymphocyte function antigen-1 (LFA-1) and its counterpart intercellular adhesion molecule-1 (ICAM-1) are prominent members of a mature IS, the effect of a small molecular inhibitor for LFA-1, BIRT377, was investigated. BIRT377 almost completely abolished the interaction forces, emphasizing the importance of LFA-1/ICAM-1-interactions for firm T-cell/ APC adhesion (see for example, the abstract at page 17852). Formation of an IS includes the coordinated translocation of several protein complexes, among others TCR and its ligand pMHC, and the integrin lymphocyte function-associated antigen-1 (LFA-1) and its counterpart intercellular adhesion molecule-1 (ICAM-1). Subsequent motor protein motion yields a cytoskeleton contraction, which exerts low forces on LFA-1 to induce occupied integrin activation and to fully arrest the two cells for adhesion. This force has to be counterbalanced on the APC side, resulting in a high interaction force between T cells and APCs. A well-studied T-cell/APC pair was selected, namely the 3B11 T hybridoma and the LK35.2 B cell line (a lymphocyte presenting an antigen/peptide at its MHC serving as an APC) because in orientating experiments 3B11 cells (T cells) could be attached well via antibodies to the cantilever of the AFM instrument. The 3B11 T hybridoma recognizes a peptide HEL35–45 derived from the model antigen hen egg lysozyme presented by Ak MHC class II positive APC (see for example, pages 17852-17853). 3B11 cells were labeled with the green dye CFSE and LK35.2 B cells were labeled with the red dye SNARF. Cells were mixed at a 1:1 ratio, centrifuged briefly, and incubated for various times before fixation with paraformaldehyde. Conjugates were identified by FACS analysis by virtue of simultaneous green and red signals. Hosseini et al analyzed whether the small molecule antagonist BIRT377, which inhibits the high-affinity state of LFA-1, would interfere with conjugate formation. Fig. 1B shows that BIRT377 blocked conjugate formation effectively. Conjugates formed also in the absence of peptide, albeit to a lower degree, and these conjugates were also blocked by BIRT377 (see for example, page 17853). Note that the phrasing that BIRT377 blocked conjugate formation (see for example, page 17853) would support that BIRT377 as contacted before and/or during conjugate formation. The cantilever attached T cell was moved near a B cell to allow for conjugate formation using forces of 1-2nN pressing the cells together, cells were then separating by retraction of the cantilever (application of force on the second cell in a direction away from the first cell) which is deemed to read upon the limitation of claim 1, step (c) (see for example, column 1 of page 17854). Hosseini et al teach incubation for complex formation at various time ranging from 0 min-60 min (see for example pages 17853-17854 and Figure 2B-C). Hosseini et al teach kinetics of conjugate formation in the presence of LFA-1 were observed in an incubation window of 0-60 min (see for example, Figure 1 and its caption at page 17853 and figure 2 and its caption at page 17854). Hosseini et al teach that the peak number of mature IS was formed after approximately 30 min (see for example, column 2 of page 17853) and that kinetics of conjugate formation in the presence of LFA-1 was observed in an incubation window of 0-60 min (see for example, figure 1 and its caption at page 17853 and figure 2 and its caption at page 17854). Hosseini et al teach that the T cell (second cell type/lymphocyte) is attached to the cantilever and the B cell (first cell type; target cell expressing antigen) is immobilized on the bottom of a petri dish (see for example, see for example, column 1 of page 17854 and figure 3 and its caption at page 17855). Hosseini et al teach cells were incubated and fixed and that BIRT377 blocked conjugate formation (cell binding) (see for example, column 1 of page 17853). Separate incubation of one or more of the cell types (B or T cells) with BIRT377 (the LFA-1 antagonist compound suspected to modulate binding of the first and second cell types) is not discussed in Hosseini et al. Moreover, where the goal is to examine the role of BIRT377 on first and second cell binding, the artisan would have found it obvious to incubate the two cell types in the presence of BIRT377. Hosseini et al teach that interaction forces are measured using deflection of a laser beam (optical) and atomic force microscopy (see for example, Figure 3 and its caption at page 17855).
Candelli et al teach a method of manipulating and/or investigating cellular bodies, comprising the steps of providing a sample comprising one or more cellular bodies in a fluid medium to be placed in a holding space with a functionalized wall surface (where the functionalized wall surface may comprise cells; see for example, lines 20-30 of page 8 of Candelli et al) to be contacted by the sample, wherein the sample is in contact with the functionalized wall surface portion (allowing for conjugate formation) during at least part of the step of application of the acoustic wave, wherein the method comprises generating an acoustic wave in the holding space exerting a force on the one or more cellular bodies of the sample in the holding space in a direction away from the functionalized wall surface portion (see for example, claim 1 of Candelli et al). Candelli et al teach that the method comprises generating an acoustic wave in the holding space exerting a force on the one or more cellular bodies of the sample in the holding space in a direction away from the functionalized wall surface portion (see for example, claim 1 of Candelli et al). Candelli et al teach incubation of T-cell engineered to express a TCR against an antigen presented on a tumor cell line where tissue expressing said tumor cell line were functionalized to the wall of the sample holder with incubation of the T cells with the functionalized wall for 30 minutes prior to application of acoustic force allowing for sorting of T cells based on avidity (see for example, line 20 of page 30 through line 11 of page 33). Candelli et al discuss the use of a sample holder where cells may be functionalized to a wall of the sample holder to be contacted with sample. Candelli et al similarly teach that detection of the cell body adhesion to the functionalized wall (which may comprise one or more cells) may be detected by optical or acoustic detection (see for example, lines 14-26 of page 9). Further, Candelli et al additionally teach screening of high-avidity T cell (lymphocytes) comprising collection of unbound T cells and collection of subsequently detached T cells after application of increasingly strong acoustic force (where cells displaced after stronger applied force would have higher avidity than unbound cells or cells detached after application of weaker acoustic force (see for example, page 32). Candelli et al teach the use of acoustic force microscopy such that the force applied between the immobilized/functionalized cell and the sample cell is an acoustic wave (see for example, the abstract, pages 1-2 and 30-33). Candelli et al teach the use of acoustic wave to screen for T cells with high avidity to a melanoma patient-derived tumor cell line where the acoustic wave increases in force over time (to allow for T cells detached from the immobilized/functionalized tumor cells by increasingly strong acoustic force (where cells requiring a strong acoustic force for detachment have higher avidity for the tumor cells) (see for example, the abstract, pages 1-2 and 30-33). Candelli et al teach that the force may be intermittently applied for intervals of 1-2 seconds or longer (see for example, pages 29-33, paying particular attention to the paragraph bridging pages 29-30) and the figures at pages 1/7-7/7).
Moy et al teach the application of atomic force microscopy to characterize the interaction between Individual pairs of living T lymphocytes (i.e., Jurkat cells) and human umbilical vein endothelial cells (HUVECs). The detachment of individual cell-cell conjugates was a complex process Involving several step-like rupture events and the viscoelastic deformation of cells on the scale of several microns. Adhesion between Jurkat cells and activated endothelial cells Increased with compression force and contact time, with the most dramatic changes occurring within the first half second of contact. After 0.25 sec of contact, E-selectin, ICAM-1, and VCAM-1 contributed to 18%, 39%, and 41% of total adhesion strength, respectively, suggesting that ICAM-1 and VCAM-1 contributed more than the selectins in supporting cell attachment (see for example, the abstract at page 1306 column 1).
It would have been prima facie obvious for a person having ordinary skill in the art to take the enumerated claims from any one of references A-I noted above (individually), directed to a method for studying cell binding/interaction/adhesion/avidity between a sample cell type(s) and a cell immobilized/functionalized on the wall surface of a sample holder where a force is applied – and:
contact the cells with an antagonist of LFA-1 such as BIRT377 as taught by Hosseini et al;
make use of an acoustic wave, generating a force on the sample cell in a direction away from the immobilized cell, where the force may be varied over time for disclosed intervals of time allowing for detection of optical traits of the cells as taught by Candelli et al; and
use human cells for the sample and/or immobilized cell as taught by Moy et al, predictably.
The artisan would have been motivated to make and use the invention as claimed because all of the references pertain to the use of force and detection/microscopy techniques to study cell-to-cell binding/adhesion/avidity where Moy et al discuss human cells and would, taken together, suggest to the artisan a reasonable expectation of success using human cells as the first, second, or both cell types to better understand the binding/adhesion/avidity in human cells. It is noted that alternative times T1, T2, T3, and T4, as recited in instant claim 4, are never disclosed as being in or being compatible for interpretation as sequential steps in a single method where T1 is chronologically before and proceeded by T2, which is chronologically before and proceeded by T3, which is chronologically before and proceeded by T4. Instead, throughout the disclosure, the time points noted as T1-T4 appear to be discreet and part of separate methods such that any one of alternatives i)-iv) of claim 4 may be independently met. This is further supported by the connection of the alternative using an ‘or’ transition term. Moreover, the drafting alternatives i)-ii) does not preclude a scenario where both cell types are independently contacted with BIRT377 (LFA-1 antagonist) prior to contacting the two cell types together. Accordingly, Hosseini et al teach cells were incubated and fixed and that BIRT377 blocked conjugate formation (cell binding) (see for example, column 1 of page 17853). This would suggest that at least 1 of the options recited in instant claim 4 at alternatives i)-iv) is met by the teachings of Hosseini et al. The individual options are merely time points obvious to the artisan to try for incubating with the LFA-1 antagonist as there are a finite number of options of time periods for incubating the cells with LFA-1 antagonist (all of which are accounted for in the recited options of i-iv of claim 4).
The MPEP provides that:
“The Supreme Court in KSR reaffirmed the familiar framework for determining obviousness as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), but stated that the Federal Circuit had erred by applying the teaching-suggestion-motivation (TSM) test in an overly rigid and formalistic way. KSR, 550 U.S. at 404, 82 USPQ2d at 1391. Specifically, the Supreme Court stated that the Federal Circuit had erred in four ways: (1) “by holding that courts and patent examiners should look only to the problem the patentee was trying to solve ” (Id. at 420, 82 USPQ2d at 1397); (2) by assuming “that a person of ordinary skill attempting to solve a problem will be led only to those elements of prior art designed to solve the same problem” (Id.); (3) by concluding “that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘obvious to try’” (Id. at 421, USPQ2d at 1397); and (4) by overemphasizing “the risk of courts and patent examiners falling prey to hindsight bias” and as a result applying “[r]igid preventative rules that deny factfinders recourse to common sense” (Id.). See also Novartis Pharms. Corp. v. West-Ward Pharms. Int'l Ltd., 923 F.3d 1051, 1059, 2019 USPQ2d 171676 (Fed. Cir. 2019); Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034, 1047-48, 120 USPQ2d 1400, 1410 (Fed. Cir. 2016); and Aventis Pharma S.A. v. Hospira, Inc., 675 F.3d 1324, 1332, 102 USPQ2d 1445, 1449 (Fed. Cir. 2012)… Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” Id. (2) “In Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., . . . [t]he two [pre-existing elements] in combination did no more than they would in separate, sequential operation.” Id. at 416-17, 82 USPQ2d at 1395. (3) “[I]n Sakraida v. AG Pro, Inc., the Court derived . . . the conclusion that when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” Id. at 417, 82 USPQ2d at 1395-96 (Internal quotations omitted.). The principles underlining these cases are instructive when the question is whether a patent application claiming the combination of elements of prior art would have been obvious. The Supreme Court further stated that:
When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions.” Id,”
(see MPEP §2141(I)).
The recited alternative time points in the process for incubation with the LFA-1 antagonist would have been prima facie to obvious to the artisan. Precedent for said obviousness may be observed in Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In reBurhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In reGibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.) (see MPEP 2144.04 IV).
With respect to instant claim 6, it is prima facie obvious to swap one known equivalent for another to achieve the same purpose, here, to examine cell-cell binding/adhesion without the influence of LFA-1/ICAM-1 interaction (see MPEP sections 2143(I)(B) and 2144.06 (II)). The artisan would have found it obvious, with a reasonable expectation of success, to modify the method of any one of references A-I according to Hosseini et al and Candelli et al to use any art-known antagonist to inhibit/reduce LFA-1/ICAM-1 interaction as taught by Hosseini et al in the portions cited above where the sample and/or immobilized cell may predictably be human as taught by Moy et al.
The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Hoffman et al (Immunol Lett. 2011 Apr 30;136(1):13-20. doi: 10.1016/j.imlet.2010.11.005. Epub 2010 Nov 26; citation 1 under Nonpatent Literature on the 04/19/202) teaches the use of single cell force spectroscopy for quantitation of interaction forces between T-cells and APCs. When T-cells were brought into contact with peptide-loaded APCs, interaction forces increased with time from about 0.5 nN after 10 s interaction to about 15 nN after 30 min. In the absence of antigen, or when ICAM-1-negative APC was used, no increase in binding forces was observed. The temporal development of interaction forces correlated with the kinetics of immune synapse formation, as determined by LFA-1 and TCR enrichment at the interface of T-cell/APC conjugates using high throughput multispectral imaging flow cytometry. Together, these results suggest that ICAM-1/LFA-1 redistribution to the contact area is mainly responsible for development of strong interaction forces. High forces will keep T-cells and APCs in tight contact, thereby providing a platform for optimal interaction between TCRs and peptide–MHC complexes (see for example, the abstract at page 13). One day before the experiment, the L-cell APCs were seeded onto round glass coverslips with a diameter of 22 mm and incubated over night to allow firm adhesion. Coverslips were then washed and mounted into the temperature controlled perfusion chamber (Biocell, JPK Instruments) of the atomic force microscopy (AFM) device. T-cells were washed twice with Hank’s buffered saline supplemented with 25 mM HEPES and flushed into the Biocell (see for example, section 2.3 at page 14).
Mai et al (An evolving new paradigm: endothelial cells – conditional innate immune cells. J Hematol Oncol 6, 61 (2013). https://doi.org/10.1186/1756-8722-6-61) teach that the endothelium participates in chronic inflammation via interactions with specialized effector cells and by acting as antigen presenting cells (APCs). Although ECs (such as HUVECs) are not professional APCs, their secondary role in antigen presentation has been recognized (see column 1 of page 4, for example).
Wang et al (The Journal of Biological Chemistry vol. 284, NO. 19, pp. 12645–12653, May 8, 2009; Doi 10.1074/jbc.M807207200) teach that the activation of LFA-1 (lymphocyte function-associated antigen) is a critical event for T cell co-stimulation. The mechanism of LFA-1 activation involves both affinity and avidity regulation. Wang et al identified antibodies that recognize and block different affinity states of the mouse LFA-1 I-domain. Monoclonal antibody 2D7 preferentially binds to the low affinity conformation, and this specific binding is abolished when LFA-1 is locked in the high affinity conformation. In contrast, M17/4 can bind both the locked high and low affinity forms of LFA-1. Although both 2D7 and M17/4 are blocking antibodies, 2D7 is significantly less potent than M17/4 in blocking LFA-1-mediated adhesion; thus, blocking high affinity LFA-1 is critical for preventing LFA-1-mediated adhesion. Using these reagents, we investigated whether LFA-1 affinity regulation affects T cell activation. Wang et al found that blocking high affinity LFA-1 prevents interleukin-2 production and T cell proliferation, demonstrated by TCR crosslinking and antigen-specific stimulation (see for example, the abstract at column 1 of page 12645).
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678