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 1-7 from the claim set dated June 30, 2023 are examined below.
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.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Giese et al. (J Biotechnol., 2010, cited in IDS filed on Aug. 16, 2023) in view of Huh et al. (Trends Cell Biol., 2011, cited in IDS filed on Aug. 16, 2023) as evidenced by Hauser et al. Semin Immunopathol., 2010, cited in IDS filed on Aug. 16, 2023).
The claims are directed to a microfluidic device that includes a body with a microchannel with a inlet and an outlet to an exterior of the body and a chamber that includes a matrix, where the chamber in fluidic communications with a microchannel, the matrix including B lymphocytes that are arranged in clusters within the matrix.
With respect to independent claim 1, Giese et al teaches that pharmaceutical drugs and compounds, including antibodies and cytokines need to be tested for their therapeutic doses and immune functionality prior to trials in humans. (Abstract; Intro, paragraph 01). However, current in vitro and animal models do not sufficiently reflect the complexity and specificity of the human immune system. (Abstract, Intro, paras. 02-05). The main structures of the secondary lymphatic organs are the primary lymphatic follicles and germinal centers (Abstract; Intro, para 09). In the secondary lymph node, B-cells are clustered in B-cell follicles in the cortex of the lymph node and are activated by direct contact with antigen or immune complexes under co-stimulation of TH4-helper cells (Intro, para. 09). B- cell follicles then change into germinal centers by induced B-cell proliferation and plasma cell
differentiation, with the formation of a dark zone (DZ), alight zone (LZ), and a mantle zone (MZ) (Intro, para 09). In B-cell proliferation, the formation of centroblast is localized to the DZ, plasma cell selection to the LZ, and finally antibody producing B-cells in the MZ (Intro, para. 09). Giese et al teaches that to remodel these lymphatic follicles in vitro, functional and structural cells, such as lymphoid cells from peripheral blood mononuclear cells (PBMCs) and stromal cells, need to be combined with artificial matrices and scaffolds to produce a suitable 3D tissue-mimicking environment (Abstract). To this end, Giese et al teaches a method for producing a human lymph node model (referred to as HuALN) (Abstract). They teach providing a device which houses 12 individually perfused miniaturized culture compartments designed for multi-parallel exposure to drugs and drug concentrations to matrix-assisted-co-cultures (2.4 Bioreactor perfusion systems, para. 06). The device includes a culture compartment with two hollow fiber membranes, one on either side of the chamber. (2.4 Bioreactor perfusion systems, para. 06). The first membrane is connected to a channel leading to a media inlet port (“first microchannel inlet,” “fluid inlet”) and a venting port (“first microchannel outlet”) (2.4 Bioreactor perfusion systems, para. 06). The second hollow fiber membrane is connected to channels leading to a media outlet port (i.e. fluid outlet) and a venting port (2.4 Bioreactor perfusion systems, para. 06). The culture compartment is also connected to a matrix port allowing liquid, gel-forming matrix-cell compositions to be added (2.4 Bioreactor perfusion systems, para. 06; Fig. 3). Giese et al teach that T and B-cells are provided to the device in a matrix-assisted culture (Results, para. 04; Fig. 8). Giese et al. teach that matrix-assisted culture resulted in the formation of B-cell clusters and the maturation of B cells up to plasma cell development (Results, para. 03-04; Fig. 8). As these cell clusters mimic B-cell follicles, they will contain less than 1% T-lymphocytes, as T-cells tend to localize to the periphery of the B-cell clusters, as evidenced by Hauser et al (Fig. 1) and demonstrated in Figure 8 of Giese et al.
Giese et al. teach their culture device is miniaturized , but do not teach a microfluidic device specifically or that the channels are microchannels.
Huh et al teaches that “organs-on-chips” permit the study of human physiology in an organ-specific context, enable development of novel in vitro disease models, and could potentially serve as replacements for animals used in drug development and toxin testing (Abstract). They teach that most studies on cell and tissue regulation have relied on the analysis of cells grown in 2D cell-culture models that fail to reconstitute the in vivo cellular microenvironment (3D cell culture, para. 02). Efforts to address these limitations have led to the development of 3D cell-culture models in which cells are grown within an extracellular matrix (ECM) (3D cell culture, para. 02). However, these models fail to reconstitute features of living organs that are crucial for their function, including tissue-tissue interfaces, spatiotemporal gradients of chemicals and oxygen, and mechanically active microenvironment that are central to the function of virtually all living organs (3D cell culture, para. 02) Huh et al teaches that microfabrication techniques from the microchip industry applied to the study human physiology could remedy such limitations (3D cell culture, para. 02). Huh et al teaches that microfabrication techniques, such as photolithograph, replica molding, and microcontact printing are well-suited to created structures with defined shapes and positions on the micrometer scale that can be used to position cells and tissues, control cell shape and function, and create highly structured 3D environments (Microengineering meets cell biology, para. 01). Microfluidics is another core microsystem that has been used to generate precisely tuned dynamic fluid flows and spatio-temporal gradients, as well as deliver nutrients and other chemical cues to cells in a controlled manner (Microengineering meets cell biology, para. 02) Complex microfluidic device have been developed to create a controlled microenvironment for the manipulation and long-term differentiation of various types of cultured cells (Microengineering cells into tissue on biochips, para. 01). Additionally, the development of polydimethylsiloxane (PDMS) microfluidic systems in combination with microfabrication techniques allowed users to create patterns and structures that provide more physiologically relevant cell culture conditions (Microengineering cells into tissue on biochips, para. 02-03). Microengineering approaches have also been used to study more complex 3D organ-level structures, such as the polarization of various epithelial cells (From 3D cultures to organs-on-a -chip). Huh et al teaches that microengineering provides a means to recapitulate organ-level functionality and that the key to meeting this challenge is to recognize the importance of reconstituting the appropriate tissue microarchitecture, biochemical milieu, and dynamic mechanical microenvironment (Potential applications and future prospects, para. 01). Lastly, Huh et al teaches that microfabrication techniques and microfluidics are well-suited to meet these challenges because they provide precise dynamic control of structure, mechanics, and chemical delivery at the cellular size scale (Potential applications and future prospects, para. 001).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to adapt the method of culturing T and B lymphocytes taught by Giese et al for a microfluidic device. One of ordinary skill in the art would have been motivated to do so as microfluidic devices provide a means for recapitulating organ-level functionality, which Giese et al and Huh et al teach are critical for capturing the complexity of in vivo organs such as the lymph node. One of ordinary skill would have a reasonable expectation of success as Huh et al teaches that microfabrication techniques and microfluidics are well-suited for the development of 3D organ-level structures. Additionally, Giese et al teaches the culture of T and B lymphocytes on a miniaturized culture device that shares many structural features with microfluidic devices, such as the use of small fluid channels, culture chambers, and the perfusion of culture media to such compartments. Therefore, one of ordinary skill in the art would reasonably expect that the method of Giese et al could be adapted for a microfluidic device.
With respect to claim 2, Giese et al teach the B lymphocyte clusters are self-organized clusters. (pg. 42, “Results”, paraz. 04-05).
With respect to claims 3-5, Giese et al teach cell clusters mimic B-cell follicles; as such, they will contain less than 1% T-lymphocytes, as T-cells tend to localize to the periphery of the B-cell clusters, as evidenced by Hauser et al (Fig. 1) and demonstrated in Figure 8 of Giese et al.
With respect to claims 6 and 7, Giese et al teach the matrix is a gelated agarose matrix (“extracellular matrix” “hydrogel”) (pg. 42, “2.5 In situ Imaging”).
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 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,406,975. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘975 patent recites methods for employing a method of using the microfluidic device of the present claims. Specifically, the method in claim 1 of the ‘975 patent teaches microfluidic device that includes a body with a microchannel with an inlet and an outlet to an exterior of the body and a chamber that includes a matrix, where the chamber in fluidic communications with a microchannel, the matrix including B lymphocytes that are arranged in clusters within the matrix. Claim 10 of the ‘975 patent teaches claim 2 of the present application. Claim 1, 17 and 18 of the ‘975 patent teach claims 3-5 of the present application. Claim 10 of the ‘975 patent teaches claim 2 of the present application.
Conclusion
No claims are allowed.
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/TERESA E KNIGHT/Primary Examiner, Art Unit 1634