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 .
Claim Status
1. The amendment filed 03/16/2016 has been entered. Claims 1, 19, 20, 23 – 28, 30, 33, 34, and 36 – 42 remain pending.
2. Claims 19, 20, 23 – 28, 30, 33, 34, and 36 – 41 are under consideration.
Election/Restrictions
3. Applicant’s election without traverse of Group II (claims 19, 20, 23 – 28, 30, and 33 – 41) in the reply filed on 11/13/2024 is acknowledged.
4. Claims 1 and 42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/13/2024.
Priority
5. This application claims priority to U.S. Provisional Patent Application Serial No. 62/860967 filed 06/13/2019.
Claim Interpretation
6. “Stabilizer” of claim 19 is interpreted as any molecule that stabilizes cross-linked blood plasma including antifibrinolytic agent based on Applicant’s specification at page 3, lines 9 – 12, page 15, lines 18 – 21, page 17, lines 3 – 14.
7. Claim 19 is interpreted as the scaffold has a tumorous pO2 level between about 1.5 kPa and about 0.2 kPa as a result of incubation in an oxygen-deprived or oxygen-enriched environment or by chemically-inducing hypoxia based on Applicant’s specification at page 10, lines 3 – 11 and page 22, lines 30 – 34 and page 23, lines 1 – 21.
Withdrawn Claim Rejections
8. The rejection of claim 30 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s arguments that state that exogenous polymer refers added from outside of the native plasma matrix at page 7.
Maintained Claim Rejections
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.
9. Claims 19, 20, 23, 24, 25, 30, and 34 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring three-dimensional cross-linked scaffold comprising peripheral blood plasma without significantly more.
The claim(s) recite(s) three-dimensional cross-linked scaffold comprising peripheral blood plasma and a stabilizer wherein the scaffold has a tumorous oxygen pO2 level between about 1.5 kPa and 0.2 kPa, which is not shown to differ from that in nature.
The Office published Office's new guidance document entitled 2019 Revised Patent Subject Matter Eligibility Guidance, published January 7, 2019. Applicant is directed to the Federal Register, Volume 4, No. 4, pages 50-57 at page 74621.
PNG
media_image1.png
570
509
media_image1.png
Greyscale
PNG
media_image2.png
358
359
media_image2.png
Greyscale
Step 1 of the USPTO' s eligibility analysis entails considering whether the claimed subject matter falls within the four statutory categories of patentable subject matter identified by 35 U.S.C. 101: Process, machine, manufacture, or composition of matter. The claims are directed to a composition of matter (step 1, Yes).
Step 2A of the 2019 Revised Patent Subject Matter Eligibility Guidance is a two-prong inquiry. In Step 2A Prong One, examiners evaluate whether the claim recites a judicial exception. The composition of matter (three-dimensional cross-linked scaffold comprising peripheral blood plasma and a stabilizer) is directed to a natural phenomenon (Step 2A, prong 1, Yes). Because the claim recites a nature-based product limitation (three-dimensional cross-linked scaffold comprising peripheral blood plasma and a stabilizer), the markedly different characteristics analysis is used to determine if the nature-based product limitation is a product of nature exception. Applicant’s specification teaches the scaffold is a tissue-like 3D scaffold that utilizes peripheral plasma as the matrix (page 5, lines 19 – 20). Applicant’s specification further teaches the peripheral plasma may be human peripheral plasma which contains fibrinogen and the cross-linker may be calcium chloride, which is naturally occurring (page 5, lines 23 – 26; page 7, lines 20 – 21;). Applicant’s specification does not define “stabilizer” but states an embodiment where “the stabilizer is selected from the group consisting of tranexamic acid, aprotinin, epsilon-aminocaproic acid, and aminomethylbenzoic acid” (page 2, lines 5 – 6 and lines 16 – 18; page 7, lines 22 – 25). While aprotinin is a product of nature, tranexamic acid, epsilon-aminocaproic acid and aminomethylbenzoic acid are synthetic derivatives of amino acids, however claim 19 does not limit the stabilizer to a non-naturally occurring compound. Further, Applicant’s specification uses the term “antifibrinolytic agents” when referring to “stabilizer” (page 3, lines 9 – 12, page 15, lines 18 – 21, page 17, lines 3 – 14). Applicant’s specification teaches an example of a human plasma 3D culture model formed through cross-linking of fibrinogen found naturally in plasma where cross-linking was achieved using three relevant cross-linkers of the blood coagulation process including thrombin, CaCl2, and Factor XIII (page 15, lines 14 – 17). Further, Applicant’s specification teaches the human plasma-derived 3D culture models were created by cross-linking fibrinogen; a blood plasma protein responsible for normal blood clotting when converted into fibrin, generating a gelatinous-like scaffold matrix (page 16, lines 20 – 24).
The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claim to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart. Here, the closest natural counterpart is naturally occurring cross-linked plasma. Gerner (Gerner, Christopher, et al. Thrombosis and haemostasis 85.03 (2001): 494-501; previously cited) teaches Factor XIII transglutaminase cross-linked fibrinogen in plasma from peripheral blood of tumor patients and in solid tumors including prostate tumors and the action of Factor XIII transglutaminase converts soft clots to hard clots by the formation of covalent [Symbol font/0x20][Symbol font/0x65]-(γ-glutamyl)lysine cross-links between fibrinogen γ-chains (Summary; page 494, right col. para. 3; page 495, right col. para. 1 – 2; page 496, left col. para. 1; page 497, right col.; page 498, right col. last para.; page 499, left col. para. 1; Figure 1, 2, 4). Factor XIII transglutaminase uses calcium ions for cross-linking as evidenced by Siebenlist (Siebenlist, Kevin R., et. al. Thrombosis and haemostasis 86.11 (2001): 1221-1228; previously cited) (Summary; page 1227, left col. para. 1). The median pO2 level in prostate tumors is 3 – 4.5 mm Hg (0.4 – 0.6 kPa) as evidenced by Parker (Parker C, et. al. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):750-7; previously cited) (Figure 1a; Table 2; Abstract; page 752, left col. para. 5; page 754, right col. para. 3). When the claimed three-dimensional cross-linked scaffold comprising peripheral blood plasma is compared to this counterpart, the comparison indicates that there are no differences in structure, function or other characteristics. Therefore, the claimed three-dimensional cross-linked scaffold comprising peripheral blood plasma is a product of nature exception and recites a judicial exception.
In Step 2A Prong Two, examiners evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. Claim 19 does not recite any additional elements and is therefore directed to the judicial exception. Claim 19 recites “a tumorous oxygen pO2 level between about 1.5 kPa and about 0.2 kPa” which Parker teaches is naturally occurring in tumors. Claims 20, 23, and 30 recite the judicial exception further comprises biological cells within the scaffold and claim 34 recites the judicial exception has an oxygen gradient. An evaluation of whether these limitations are insignificant extra-solution activity is then performed. Note that because Step 2A Prong Two analysis excludes consideration of whether a limitation is well-understood, routine, conventional activity, this evaluation does not take into account whether or not the limitation is well-known. When so evaluated, these additional elements are insignificant extra-solution activity because the pO2 level is found in tumors containing biological cells , “biological cells” and “oxygen gradient” are recited so generically. The claims do not recite what the biological cells or oxygen gradient are or how the scaffold comprising the biological cells or oxygen gradient are formed. Therefore, the claims cover any possible biological cells and any type of oxygen gradient and fails to meaningfully limit the claim because it is at best the equivalent of merely adding the words “apply it” to the judicial exception. Further, the concentration of cells would not meaningfully limit the claims. Accordingly, the biological cells and oxygen gradient do not integrate the recited judicial exception into a practical application and the claims are therefore directed to the judicial exception (Step 2A, prong 2, No).
In Step 2B, the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements adds an inventive concept into the claim. As discussed with respect to Step 2A Prong Two, claim 10 does not recite any additional limitations and the limitations recited in claims 20, 23, 30, and 34 regarding biological cells or oxygen gradient are at best the equivalent of merely adding the words “apply it” to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept. At Step 2B, the evaluation of the insignificant extra-solution activity consideration takes into account whether or not the extra-solution activity is well-known. Here, recitation of the judicial exception further comprising biological cells or having an oxygen gradient are recited at a high level of generality and does not amount to significantly more and does not provide an inventive concept (Step 2B: No).
In the instant case, the limitations of the claims do not impose limits on the claim scope such that they are not markedly different in structure from a naturally occurring product.
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.
10. Claim(s) 19, 20, 23 – 28, 30, 33, 34, and 37 remain rejected under 35 U.S.C. 103 as being unpatentable over Gerner (Gerner, Christopher, et al. Thrombosis and haemostasis 85.03 (2001): 494-501; previously cited), hereinafter Gerner as evidenced by Parker (Parker C, et. al. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):750-7; previously cited), hereinafter Parker and Siebenlist (Siebenlist, Kevin R., et. al. Thrombosis and haemostasis 86.11 (2001): 1221-1228; previously cited), hereinafter Siebenlist in view of de la Puente (de la Puente, Pilar, et al. Biomaterials 73 (2015): 70-84; previously cited), hereinafter de la Puente, which is cited on the IDS filed 11/17/2021 in view of Shiozawa (Shiozawa, Yusuke, et al. The Journal of clinical investigation 121.4 (2011): 1298-1312; previously cited), hereinafter Shiozawa.
Regarding claim 19, Gerner teaches Factor XIII transglutaminase cross-linked fibrinogen in plasma from peripheral blood of tumor patients and in solid tumors including prostate tumors (“three-dimensional cross-linked scaffold comprising peripheral blood plasma from one or more subjects having a tumor”) and the action of Factor XIII transglutaminase converts soft clots to hard clots by the formation of covalent [Symbol font/0x20][Symbol font/0x65]-(γ-glutamyl)lysine cross-links between fibrinogen γ-chains (“stabilizer”) (Summary; page 494, right col. para. 3; page 495, right col. para. 1 – 2; page 496, left col. para. 1; page 498, right col. last para.; page 499, left col. para. 1 and right col. para. 2; Figure 1, 2, 4; page 497, right col.). Localized prostate cancer is characterized by marked hypoxia and the median pO2 level in prostate tumors is 3 – 4.5 mm Hg (0.4 – 0.6 kPa) (“a tumorous oxygen pO2 level between about 1.5 kPa and about 0.2 kPa”) as evidenced by Parker (Figure 1a; Table 2; Abstract; page 750, right col. para. 1; page 752, left col. para. 5; page 754, right col. para. 3; page 756, left col. para. 2).
Regarding claim 20, Gerner teaches fibrinogen gamma-chain dimer in solid tumors (“biological cells within the scaffold”) including prostate tumors (Summary; Figure 1 – 2; page 495, right col. para. 1; page 497, right col.; page 498, right col. last para.).
Regarding claim 24, Gerner teaches the cross-linked fibrin is the result of Factor XIII transglutaminase (Summary; page 494, right col. para. 3; page 495, right col. para. 1 – 2; page 496, left col. para. 1; page 498, right col. last para.; page 499, left col. para. 1; Figure 1, 2, 4; page 497, right col.). Factor XIII transglutaminase uses calcium ions for cross-linking as evidenced by Siebenlist (Summary; page 1227, left col. para. 1).
Regarding claim 37, Gerner teaches fibrinogen gamma-chain dimer in solid tumors (“biological cells within the scaffold”) including prostate tumors (Summary; Figure 1 – 2; page 495, right col. para. 1; page 497, right col.; page 498, right col. last para.). Localized prostate cancer is characterized by marked hypoxia and the median pO2 level in prostate tumors is 3 – 4.5 mm Hg (0.4 – 0.6 kPa) (“a tumorous oxygen pO2 level between about 1.5 kPa and about 0.2 kPa”) as evidenced by Parker (Figure 1a; Table 2; Abstract; page 750, right col. para. 1; page 752, left col. para. 5; page 754, right col. para. 3; page 756, left col. para. 2).
Gerner does not teach a concentration of biological cells of claim 23 and 30 or a concentration of calcium chloride of claim 25 and 28 or “tranexamic acid” of claim 26 or a concentration of tranexamic acid of claim 27 and 28 or scaffold thickness of claim 33. However, Gerner teaches high transglutaminase activity may be associated with cancer as cross-linked fibrinogen was found in plasma from tumor patients but not in plasma from controls and patients suffering acute infections and/or inflammations (Summary; page 499, left col. para. 1). Gerner teaches fibrin deposition has been described in tumor stroma and at the tumor periphery (page 494, left col.). Gerner teaches about half of all cancer patients exhibit abnormalities in one or more routine coagulation parameters (page 494, left col.). Gerner teaches in mammary carcinoma a tissue factor expressed by tumor-associated vascular endothelial cells promotes activation of thrombin and subsequent polymerization of fibrinogen to fibrin (page 494, left col. and right col. para. 1). Gerner teaches elevated amounts of coagulation activation markers were described in tumor patients and metastatic melanoma cells were reported to support greater coagulant activity than primary cells in vitro (page 494, right col. para. 2). Gerner teaches fibrin deposits occur in various human cancers where fibrin originates from the blood (page 494, right col. para. 3). Gerner teaches significantly elevated amounts of crosslinked fibrinogen dimer in plasma from breast, lung, and prostate cancer patients (page 499, right col. para. 2). Gerner teaches the presence of hard clots in tissue samples from six different types of cancer (page 499, right col. para. 2; Figure 2). Gerner teaches altered fibrin turnover may be responsible for tumor-promoting effects by various means (page 499, right col. last para.). Gerner teaches metastasizing tumor cells were described to be able to generate a protein coat make of platelets and fibrin providing protection against the attack of natural killer cells (page 499, right col. last para.; page 500, left col. para. 1).
Regarding claim 23 and 26, de la Puente a scaffold of cross-linked peripheral blood plasma from cancer patients and tranexamic acid (“tranexamic acid” of claim 26) comprises 30,000 cells/well in 0.05 mL which is 60 x 103 cells/mL (claim 23) (page 71, right col. paragraph 2; page 73, left col. paragraph 2; page 74, right col. paragraph 1).
Regarding claim 25, de la Puente teaches the scaffold comprises 1 mg/ml calcium chloride (page 71, right col. paragraph 2).
Regarding claim 27, de la Puente teaches the scaffold comprises 4 mg/ml tranexamic acid (page 71, right col. paragraph 2).
Regarding claim 28, de la Puente teaches the scaffold comprises 1 mg/ml calcium chloride and 4 mg/ml tranexamic acid (“between about 0.5 mg/ml and about 5 mg/ml” and “between about 0.5 mg/ml and about 10 mg/mL” of “I” and “between about 0.5 mg/ml and about 2.5 mg/ml” and “about 5 mg/ml” of “II”) (page 71, right col. paragraph 2).
Regarding claim 30, de la Puente teaches 6 x 104 cells/ml (“(a)”), no exogenous polymer was included in the scaffold (“(b)”), and 40% plasma present in the mixture (“(c)”) (page 71, right col. paragraph 2; page 73, left col. paragraph 2; page 74, right col. paragraph 1; page 77, left col. paragraph 2).
Regarding claim 33, de la Puente teaches a scaffold thickness of about 400 µm in Figure 1Biv and 2B.
Regarding claim 34, de la Puente teaches the scaffold has an oxygen gradient where there was a significant increase in hypoxia in the bottom layer compared to the top layer (page 75, left col. paragraph 5; Figure 4Ai).
De la Puente teaches a discrepancy between in vitro efficacy and clinical outcomes of myeloma drugs can be attributed to limitations of classic 2D tissue culture and drug screening models (page 70, left col. para. 2 and right col. para. 1). De la Puente teaches 2D tissue culture systems cannot reproduce the oxygen and drug gradients found in the bone marrow niche which limits the ability of 2D cultures to accurately predict drug sensitivity (page 70, right col. para. 1). De la Puente teaches there is an urgent need to develop a model that addresses these limitations to investigate biological mechanisms and drug resistance that are relevant and translatable to improved patient response (page 70, right col. para. 1). De la Puente teaches the 3DTEBM cultures recreated oxygen gradients throughout the depth of the scaffold (page 79, right col. paragraph 1; Figure 6). De la Puente teaches the 3DTEBM cultures allowed proliferation of MM cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche such as oxygen and drug gradients, and induced drug resistance in MM cells more than 2D or commercial 3D tissue culture systems (Abstract). One would have been motivated to combine the teachings of Gerner and de la Puente as Gerner teaches the presence of crosslinked fibrinogen in tumors and de la Puente teaches crosslinked fibrinogen supports cancer cell growth.
Shiozawa teaches a large proportion of solid tumor metastases are bone metastases that establish footholds in the bone marrow (Abstract). Shiozawa teaches human prostate cancer cells directly compete with hematopoietic stem cells (HSCs) for occupancy of the HSC niche and the HSC niche serves as a direct target for prostate cancer during dissemination and plays a central role in bone metastases (Abstract; page 1298, left col. para. 3 and right col. para. 1; Figure 9; page 1309, left col. last para. and right col. para. 1). Shiozawa teaches little is known about the postdissemination and niche engagement events activated by prostate cancer cells to coopt the HSC niche (page 1309, right col. para. 2). Shiozawa teaches it is possible that disseminated tumor cells proliferate slowly over time, the capacity of the niche is overwhelmed, leading to clinically relevant disease (page 1309, right col. para. 2). Shiozawa teaches their findings has the potential to facilitate better understanding of the molecular events involved in bone metastases and to lead to new therapeutic avenues for an incurable disease (page 1309, right col. para. 4). Shiozawa teaches metastases represent the most common malignant tumors involving the skeleton where nearly 70% of prostate cancer and breast cancer patients and 15% - 30% of patients with lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney cancer have bone lesions (page 1298, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Gerner regarding cross-linked fibrinogen in peripheral blood plasma from patients with cancer and in their tumors with the teachings of de la Puente regarding a 3D scaffold comprising peripheral blood plasma from multiple myeloma patients and a stabilizer and further comprising 60 x 103 cells/mL biological cells with the teachings of Shiozawa regarding human prostate cancer cells migrate to the bone marrow to arrive at the claimed 3D scaffold comprising peripheral blood plasma from cancer patients with solid tumors, tranexamic acid, and a tumorous pO2 level between about 1.5 kPa and about 0.2 kPa. One would have been motivated to combine the teachings of Gerner, de la Puente, and Shiozawa in a 3D scaffold comprising peripheral blood plasma from one or more subjects having cancer to study bone metastases of solid tumors and evaluate tumor therapies as Gerner teaches altered fibrin turnover may be responsible for tumor-promoting effects by various means and de la Puente teaches there is an urgent need to develop a model that addresses the limitations of 2D culture systems to investigate biological mechanisms and drug resistance that are relevant and translatable to improved patient response and Shiozawa teaches a large proportion of solid tumor metastases are bone metastases that establish footholds in the bone marrow and Shiozawa teaches little is known about the postdissemination and niche engagement events activated by prostate cancer cells to coopt the HSC niche and Shiozawa teaches metastases represent the most common malignant tumors involving the skeleton where nearly 70% of prostate cancer and breast cancer patients and 15% - 30% of patients with lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney cancer have bone lesions. One would have a reasonable expectation of success in combining the teachings as Gerner teaches the presence of crosslinked fibrin in tissue samples from six different types of cancer and de la Puente teaches the 3DTEBM cultures allowed proliferation of cancer cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche such as oxygen and drug gradients and Shiozawa teaches human prostate cancer cells directly compete with HSCs for occupancy of the HSC niche and the HSC niche serves as a direct target for prostate cancer during dissemination and plays a central role in bone metastases.
11. Claim(s) 36 remains rejected under 35 U.S.C. 103 as being unpatentable over Gerner (Gerner, Christopher, et al. Thrombosis and haemostasis 85.03 (2001): 494-501; previously cited), hereinafter Gerner as evidenced by Parker (Parker C, et. al. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):750-7; previously cited), hereinafter Parker and Siebenlist (Siebenlist, Kevin R., et. al. Thrombosis and haemostasis 86.11 (2001): 1221-1228; previously cited), hereinafter Siebenlist in view of de la Puente (de la Puente, Pilar, et al. Biomaterials 73 (2015): 70-84; previously cited), hereinafter de la Puente, which is cited on the IDS filed 11/17/2021 in view of Shiozawa (Shiozawa, Yusuke, et al. The Journal of clinical investigation 121.4 (2011): 1298-1312; previously cited), hereinafter Shiozawaas applied to claims 19, 20, 23 – 28, 30, 33, 34, and 37 above, and further in view of Ma (Ma, T., et. al. BMC Res Notes 8, 687 (2015)), hereinafter Ma in view of Demol (Demol, Jan, et al. Biomaterials 32.1 (2011): 107-118; previously cited), hereinafter Demol.
Gerner in view of de la Puente and Shiozawa make obvious the limitations of claim 19 as set forth above.
Gerner teaches crosslinked fibrin in prostate tumor samples (Figure 2) and prostate tumors can have heterogeneity in oxygenation with pO2 values ranging from 0.2 to 57.3 mm Hg (0.02 to 7.63 kPa) as evidenced by Parker (Abstract; page 752, left col. para. 5; Table 2). De la Puente teaches the scaffold comprises endothelial cells (“non-tumor biological cells”) and an oxygen gradient (page 73, left col. paragraph 1 – 2). De la Puente teaches culturing 2D cultures under normoxic (21% O2) or hypoxic (1% O2) conditions in the hypoxic chamber (page 74, left col. para. 6). De la Puente teaches the bone marrow niche is a 3D structure and oxygen gradients develop in the bone marrow during the progression of MM, which include metastasis (page 79, left col. paragraph 2; Figure 6). De la Puente teaches their scaffold to model MM is reproducible, fast, not technically challenging and simulates 3D aspects of the bone marrow niche such as hypoxia (page 77, left col. paragraph 1). Shiozawa teaches prostate cancer cells bind to osteoblasts (page 1307, right col. para. 2). Shiozawa teaches preosteoblasts are critical compartment of the HSC niche but further studies are needed to determine whether preosteoblasts serve as the solid tumor niche (page 1309, right col. para. 2 2).
Ma teaches culturing prostate cancer cells at 2 kPa and 20 kPa where the value of hypoxia affects the cellular and antigenic landscape of the cells (Abstract; page 3, left col. para. 2; page 4, right col. last para.; Figure 1; page 6, left col. para. 2 and right col. 1 – 3; page 9). Ma teaches by modifying the immune reactivity of prostate cancer cells in culture, manipulation of pO2 can be proposed as a new avenue for improving diagnosis, prognosis, and immunotherapy for prostate cancer (Abstract). Ma teaches prostate cancer is the second most common cancer in men worldwide and metastatic prostate cancer is not curable by surgery and is resistant to chemotherapy and ionizing radiation (page 1, left col.). Ma teaches similar to most solid tumors, prostate cancer tissues are characterized by low oxygen tension that is a marker of poor clinical prognosis (page 1, left col.). Ma teaches it has generally been accepted that microenvironmental hypoxia is among the reasons for resistance to treatment (page 1, right col.). Ma teaches changes in pO2 modulate innate and adaptive immunity (page 2, left col. para. 2). Ma teaches low pO2 is commonly associated with tumor aggressiveness (page 10, left col.).
Demol teaches a model of oxygen tensions throughout a fibrin scaffold comprising non-tumor cells where the fibrin scaffold was prepared with tranexamic acid (Abstract; page 109, right col. para. 4; Figure 2; page 116, left col. para. 2 – 4 and right col. para. 2; page 117, left col. para. 3). Demol teaches the model shows the oxygen tension ranging from anoxia to hypoxia to normoxia (0% to 21%) in the fibrin hydrogel with cells (Figure 5 – 9; page 113, right col. para. 2; page 114, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Gerner regarding cross-linked fibrinogen in peripheral blood plasma from patients with cancer and in their tumors with the teachings of de la Puente regarding a 3D scaffold comprising peripheral blood plasma from multiple myeloma patients, a stabilizer, and 60 x 103 cells/mL non-tumor cells where the gradient has an oxygen gradient with the teachings of Shiozawa regarding human prostate cancer cells migrate to the bone marrow and bind to osteoblasts with the teachings of Ma regarding culturing prostate cancer cells at 2 kPa and 20 kPa affects the cellular and antigenic landscape of the cells with the teachings of Demol regarding a 3D fibrin scaffold with tranexamic acid and cells with various oxygen tensions throughout the scaffold to arrive at the claimed 3D scaffold comprising non-tumor biological cells and wherein the pO2 level is between about 8.6 kPa and about 2.5 kPa. One would have been motivated to combine the teachings of Gerner, de la Puente, Shiozawa, Ma, and Demol in a scaffold with an oxygen gradient to study bone metastases of solid tumors and evaluate tumor therapies as Ma teaches prostate cancer is the second most common cancer in men worldwide and metastatic prostate cancer is not curable by surgery and is resistant to chemotherapy and ionizing radiation and Ma teaches similar to most solid tumors, prostate cancer tissues are characterized by low oxygen tension that is a marker of poor clinical prognosis. One would have a reasonable expectation of success in combining the teachings as Ma teaches culturing prostate cancer cells at 2 kPa and 20 kPa where the value of hypoxia affects the cellular and antigenic landscape of the cells and Ma teaches low pO2 is commonly associated with tumor aggressiveness and Demol teaches oxygen tension ranging from anoxia to hypoxia to normoxia (0% to 21%) in the fibrin hydrogel with cells.
12. Claim(s) 38 – 40 remain rejected under 35 U.S.C. 103 as being unpatentable over Gerner (Gerner, Christopher, et al. Thrombosis and haemostasis 85.03 (2001): 494-501; previously cited), hereinafter Gerner as evidenced by Parker (Parker C, et. al. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):750-7; previously cited), hereinafter Parker and Siebenlist (Siebenlist, Kevin R., et. al. Thrombosis and haemostasis 86.11 (2001): 1221-1228; previously cited), hereinafter Siebenlist in view of de la Puente (de la Puente, Pilar, et al. Biomaterials 73 (2015): 70-84; previously cited), hereinafter de la Puente, which is cited on the IDS filed 11/17/2021 in view of Shiozawa (Shiozawa, Yusuke, et al. The Journal of clinical investigation 121.4 (2011): 1298-1312; previously cited), hereinafter Shiozawaas applied to claims 19, 20, 23 – 28, 30, 33, 34, and 37 above, and further in view of Duong (Duong, H, et. al. Tissue Engineering Part A 15.7 (2009): 1865-1876; previously cited), hereinafter Duong as evidenced by Bahlis (Bahlis, NJ., et al. Leukemia & lymphoma 46.6 (2005): 899-908; previously cited), hereinafter Bahlis.
Gerner in view of de la Puente and Shiozawa make obvious the limitations of claim 19 as set forth above. Gerner, de la Puente, and Shiozawa do not teach the claimed stiffness of claim 38, 39, or 40.
Regarding claim 39, de la Puente teaches the scaffold comprises endothelial cells (page 73, left col. paragraph 1 – 2) but does not teach the claimed stiffness.
Regarding claim 40, Gerner teaches the cross-linked fibrin is present in solid tumors including prostate tumors (Figure 2) but does not teach stiffness. de la Puente teaches the scaffold comprises multiple myeloma cells and an oxygen gradient (page 73, left col.; Figure 6) but does not teach the claimed stiffness.
De la Puente teaches the scaffold was developed through cross-linking of fibrinogen naturally found in the plasma of peripheral blood (page 71, right col. paragraph 2). De la Puente teaches fibrin-based scaffolds have been used as 3D systems for cell culture and are characterized by safety, manageability, biocompatibility, and reproducibility and is an excellent scaffold for tissue engineering techniques (page 77, left col. last paragraph). De la Puente teaches fibrin-based scaffolds made from patient-derived plasma contains molecules that help cellular adhesion and is a reservoir for growth factors, platelet, cytokines and enzymes from the own patient (page 77, right col. paragraph 1). De la Puente teaches developing 3D cross-linked scaffolds from individual MM patients to perform drug screens for each patient and develop personalized therapeutic strategies (page 82, left col. paragraph 1). Shiozawa teaches their findings that human prostate cancer cells target the HSC niche to establish footholds in bone marrow has the potential to facilitate better understanding of the molecular events involved in bone metastases and to lead to new therapeutic avenues for an incurable disease (page 1309, right col. para. 4).
Regarding “stiffness between about 0.5 kPa to 7 kPa” of claims 38 – 40, Duong teaches a 3D cross-linked fibrin matrix with stiffness values from about 0.5 kPa to 4.5 kPa depending on the concentration of fibrinogen and thrombin (Figure 2; page 1868, left col. last paragraph; Figures 7 and 8). Duong teaches the matrix was formed from human fibrinogen and cross-linked with thrombin and calcium chloride (page 1866, left col. paragraph 3). Duong teaches a 3D cross-linked fibrin matrix comprising normal human fibroblasts with stiffness values from about 0.3 kPa to 1 kPa depending on the seeding density and culture time (Figures 7 and 8). Duong teaches treating cells with staurosporine which stopped cell spreading to show that cell spreading does contribute to the stiffness of the matrix (page 1874, right col. paragraph 1; Figure 9B). Staurosporine and derivatives of staurosporine kill MM cells as evidenced by Bahlis (Abstract). Duong teaches fibroblasts developed spreading morphology when grown on surfaces with a stiffness of greater than 2 kPa and that different cell types may prefer different stiffness for their growth and survival (page 1875, left col. paragraph 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Gerner regarding cross-linked fibrinogen in peripheral blood plasma from patients with cancer and in their tumors with the teachings of de la Puente regarding a 3D scaffold comprising peripheral blood plasma from MM patients, a stabilizer, tumor cells, and non-tumor cells with the teachings of Shiozawa regarding human prostate cancer cells migrate to the bone marrow with the teachings of Duong regarding fibrinogen cross-linked matrices with stiffness between about 0.5 to 4.5 kPa to arrive at the claimed invention where the scaffold comprises a stiffness between about 0.5 to 4.5 kPa. One would have been motivated to combine the teachings of Gerner, de la Puente, Shiozawa, and Duong in a scaffold with an oxygen gradient to study bone metastases of solid tumors and evaluate tumor therapies as de la Puente teaches the discrepancy between preclinical and clinical outcomes can be attributed to the failure of classic 2D culture models to accurately recapitulate the drug responses observed in patients and Shiozawa teaches their findings that human prostate cancer cells target the HSC niche to establish footholds in bone marrow has the potential to facilitate better understanding of the molecular events involved in bone metastases and to lead to new therapeutic avenues for an incurable disease and Duong teaches different cell types may prefer different stiffness for their growth and survival. One would have a reasonable expectation of success in combining the teachings as Gerner teaches the presence of crosslinked fibrin in solid tumors and de la Puente teaches the 3DTEBM cultures allowed proliferation of cancer cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche such as oxygen and drug gradients and Duong teaches the matrix stiffness is adjustable.
13. Claim(s) 41 remains rejected under 35 U.S.C. 103 as being unpatentable over Gerner (Gerner, Christopher, et al. Thrombosis and haemostasis 85.03 (2001): 494-501; previously cited), hereinafter Gerner as evidenced by Parker (Parker C, et. al. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):750-7; previously cited), hereinafter Parker and Siebenlist (Siebenlist, Kevin R., et. al. Thrombosis and haemostasis 86.11 (2001): 1221-1228; previously cited), hereinafter Siebenlist in view of de la Puente (de la Puente, Pilar, et al. Biomaterials 73 (2015): 70-84; previously cited), hereinafter de la Puente, which is cited on the IDS filed 11/17/2021 in view of Shiozawa (Shiozawa, Yusuke, et al. The Journal of clinical investigation 121.4 (2011): 1298-1312; previously cited), hereinafter Shiozawaas applied to claims 19, 20, 23 – 28, 30, 33, 34, and 37 , and further in view of Yayon (US-20060019389-A1; Filed 07/22/2004, Published 01/26/2006; previously cited), hereinafter Yayon.
Gerner in view of de la Puente and Shiozawa make obvious the limitations of claim 19 as set forth above. De la Puente teaches the 3D scaffold structure of fibrin for cell culture is composed of a network of interconnected pores through which cells activity migrate, multiply and spread along the scaffold, the diffusion of nutrients and waste products is facilitated, and vascularization is promoted and developed (page 77, right col. paragraph 1). Gerner, de la Puente, and Shiozawa do not teach the claimed porosity of claim 41.
Yayon teaches a scaffold comprising cross-linked plasma obtained from a patient and the scaffold can comprise aprotinin, tranexamic acid, or epsilon-aminocaproic where plasma cross-linked matrix with pore diameters of 9, 10, 14, and 16 µm (Table 2; page 11, 0164; page 12, 0177; page 17, 0242 and 0244; Figure 1 and 7). Yayon teaches porous structures are useful for supporting cell growth in vitro (page 1, 0005). Yayon teaches fibrinogen is a major plasma protein and in the presence of calcium ions and thrombin forms a glue useful for tissue culture (page 1, 0009). Yayon teaches there remains an unmet need for a natural, three dimensional matrix that integrates a matrix having optimal pore size , pore distribution, and interconnected channels for cell maintenance and nutrient diffusion while it provides a structural support (page 1, 0024).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Gerner regarding cross-linked fibrinogen in peripheral blood plasma from patients with cancer and in their tumors with the teachings of de la Puente regarding a porous fibrin scaffold with the teachings of Yayon regarding a porous fibrin scaffold with pore diameters of 9, 10, 14, and 16 µm to arrive at the claimed scaffold where the porosity is between 0.5 µm and about 20 µm. One would have been motivated to combine the teachings of Gerner, de la Puente, Shiozawa, and Yayon in a scaffold with an oxygen gradient to study bone metastases of solid tumors and evaluate tumor therapies where cell growth is supported as Yayon teaches there remains an unmet need for a natural, three dimensional matrix that integrates a matrix having optimal pore size , pore distribution, and interconnected channels for cell maintenance and nutrient diffusion while it provides a structural support. One would have a reasonable expectation of success in combining the teachings as both de la Puente and Yayon teach the scaffold comprises fibrinogen and tranexamic acid and de la Puente teaches the 3D scaffold structure of fibrin for cell culture is composed of a network of interconnected pores through which cells activity migrate, multiply and spread along the scaffold, the diffusion of nutrients and waste products is facilitated, and vascularization is promoted and developed.
Maintained 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.
14. Claims 19, 20, 23 – 28, 30, and 33 – 41 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19, 20, 22 – 25, 27 – 33, 35, and 36 of copending Application No. 17612147 (reference application) in view of de la Puente (de la Puente, Pilar, et al. Biomaterials 73 (2015): 70-84; previously cited), hereinafter de la Puente, which is cited on the IDS filed 11/17/2021
Claims 19, 20, 22 – 25, 27 – 33, 35, and 36 of the reference application are drawn to a three-dimensional cross-linked scaffold comprising cord blood plasma from a subject having a maternal pregnancy complication and/or from a subject having a fetal pregnancy complication, and tranexamic acid. Claims 19, 20, 23 – 28, 30, and 33 – 41 of the instant application are drawn to a three-dimensional cross-linked scaffold comprising peripheral blood plasma from one or more subjects having a tumor, and a stabilizer, wherein the scaffold has a tumorous oxygen pO2 level between about 1.5 kPa and about 0.2 kPa. The instant claims and co-pending claims differ in the origin of the plasma and the instant claims recite a pO2 level that is not recited in the co-pending claims. The instant claims recite a generic “stabilizer” while the co-pending claims recite “tranexamic acid”.
Co-pending claim 19 recites cord blood plasma. Co-pending claim 19 lacks peripheral blood plasma of instant claim 19. De la Puente teaches a scaffold of cross-linked peripheral blood plasma from patients with multiple myeloma patients and tranexamic acid (page 71, right col. paragraph 2). De la Puente teaches oxygen gradients (hypoxia) developed in the bone marrow during the progression of multiple myeloma (MM) which induced metastasis and drug-resistance in MM cells in vitro and in vivo (page 79, left col. last paragraph). De la Puente teaches 2D and 3D models that grow MM cell on top of a polymer surface or bone chip lack the development of drug gradients and hypoxia; therefore, these will not accurately depict proliferation and drug resistance of MM cells in the bone marrow niche (page 79, left col. last paragraph). De la Puente teaches the discrepancy between preclinical and clinical outcomes can be attributed to the failure of classic 2D culture models to accurately recapitulate the complex biology of MM and drug responses observed in patients (Abstract; page 70, left col. paragraph 1 and right col. paragraph 1; page 75, right col. paragraph 6 – 7). De la Puente teaches the 3DTEBM cultures allowed proliferation of MM cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche such as oxygen and drug gradients, and induced drug resistance in MM cells more than 2D or commercial 3D tissue culture systems (Abstract). De la Puente teaches MM is the second most prevalent hematological malignancy and remains incurable with a median survival time of 3 – 5 years (page 70, left col. paragraph 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to substitute the cord blood plasma of the reference application with peripheral blood plasma of de la Puente. One would have been motivated to make the substitution in a scaffold comprising peripheral blood plasma from a patient with multiple myeloma tumor cells to evaluate cancer drugs because De la Puente teaches the discrepancy between preclinical and clinical outcomes can be attributed to the failure of classic 2D culture models to accurately recapitulate the complex biology of MM and drug responses observed in patients. One would have a reasonable expectation of success in making the substitution as De la Puente teaches the 3DTEBM cultures allowed proliferation of MM cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche such as oxygen and drug gradients, and induced drug resistance in MM cells more than 2D or commercial 3D tissue culture systems.
This is a provisional nonstatutory double patenting rejection.
Applicant Arguments/ Response to Arguments
15. Applicant Argues: On page 7, Applicant asserts that “exogenous” of claim 30 means added from outside of the native plasma matrix regarding the rejection of claim 30 under 35 U.S.C. 112(b).
Response to Arguments: The rejection of claim 30 under 112(b) has been withdrawn in view of Applicant’s arguments.
Applicant Argues: On page 8, para. 2 – 4 and page 9, para. 1, Applicant disagrees with the rejection of claims 19, 20, 23, 24, 25, 30, and 34 under 35 U.S.C. 101 because Applicant disagrees that Gerner’s in vivo fibrin deposition and fibrinolysis in circulating plasma or tumor tissue provide an analogue to the claimed engineered scaffolds and the reference does not teach fabrication of a three-dimensional cell culture scaffold, does not describe any deliberate engineering of pore structure, stiffness, stability or oxygen environment, and does not disclose the use of such structures as ex vivo tumor models for drug response prediction.
Response to Arguments: This is not found persuasive because the claims are drawn to a composition and not a method of fabrication of a three-dimensional cell culture scaffold or a method of drug response prediction. The rejected claims do not recite structural limitations that distinguish the claimed cross-linked scaffold from the naturally occurring scaffold of Gerner. Should Applicant amend claim 19 to recite a stabilizer that is not found naturally occurring with cross-linked blood plasma (see claim 26), the rejection may be overcome upon further consideration.
Applicant Argues: On page 9, para. 2 – 4, Applicant asserts that in the Examiner allegedly undermines any reliance on synthetic antifibrinolytics as a distinguishing element in the “Response to Arguments” in the previous Office Action. Applicant asserts that the scaffold of Gerner is not formed into controlled 3D constructs with specified pore sizes or mechanical properties and it is continually subject to active fibrinolysis, whereas the claimed scaffolds are intentionally fabricated with defined geometry and culture-ready form which are marked differences. Applicant asserts that the claims are not limited to naturally occurring aprotinin and they encompass synthetic small-molecule antifibrinolytics such as tranexamic acid. On page 10, Applicant asserts that Parker does not describe or suggest any in vitro three-dimensional scaffold, let alone a scaffold prepared from peripheral blood plasma, stabilized, and used as a tumor culture and drug-testing model. Applicant asserts that an ex vivo scaffold engineered to reproduce and control clinically relevant oxygen range is not a product of nature. Applicant asserts that under CellzDirect and related decisions, such a new and improved way of modeling human disease and drug response is not an ineligible natural product but a patent-eligible technological advance. On page 11, Applicant asserts that the claims integrate any implicated natural phenomenon into a practical application: a three-dimensional, patient-specific tumor model that addresses well-documented limitations of 2D and prior 3D systems and achieves substantially improved clinical predictive value.
Response to Arguments: Claim 19 broadly recites “stabilizer” and does not recite that the stabilizer is synthetic and Applicant’s specification does not define “stabilizer” as synthetic and as Applicant states, the claim encompasses naturally and synthetic stabilizers. Claim 19 does not recite physical or mechanical properties of the claimed scaffold that distinguish it from the naturally occurring counterpart. The Parker reference teaches that the naturally occurring counterpart in vivo exists in the claims pO2 range and therefore the claim reads on a product of nature. The claims are not drawn to a method of measuring drug responses and while that may be Applicant’s intended use of the claimed scaffold, the claims are drawn to a composition that has a naturally occurring counterpart and the claimed composition is not shown to differ from this naturally occurring counterpart. Therefore, the rejection is maintained. Should Applicant amend claim 19 to recite a stabilizer that is not found naturally occurring with cross-linked blood plasma (see claim 26), or physical or mechanical properties that distinguish the claimed scaffold from the naturally occurring counterpart, the rejection may be overcome upon further consideration.
Applicant Argues: On page 12 and page 13, para. 1 – 3, Applicant asserts that Gerner does not form scaffolds, does not describe ex vivo culture of tumor cells, and does not suggest harvesting peripheral blood plasma from solid-tumor patients to build 3D culture platforms. Applicant asserts that de la Puente’s model is based on bone marrow plasma, not peripheral blood plasma from solid-tumor patients and one of ordinary skill would recognize that such an invasive procedure would not be undertaken for a typical solid-tumor patient. Applicant asserts that Parker does not suggest building any in vitro scaffolds. Applicant asserts Siebenlist does not perform crosslinking in patient-derived plasma matrices designed for cell culture. Applicant asserts that Shiozawa does not describe plasma scaffold engineering. Applicant assert that there is no articulated rationale explaining why a POSITA would be motivated to create the claimed combination and a POSITA would not reasonably expect the combination would produce advantages described in a method of drug screening.
Response to Arguments: This is not found persuasive because the claims are drawn to a composition and not a method of making the claimed composition and Gerner teaches Factor XIII transglutaminase cross-linked fibrinogen in plasma from peripheral blood of tumor patients and in solid tumors including prostate tumors. De la Puente teaches a discrepancy between in vitro efficacy and clinical outcomes of myeloma drugs can be attributed to limitations of classic 2D tissue culture and drug screening models (page 70, left col. para. 2 and right col. para. 1). De la Puente teaches there is an urgent need to develop a model to investigate biological mechanisms and drug resistance that are relevant and translatable to improved patient response (page 70, right col. para. 1). De la Puente teaches the 3DTEBM cultures recreated oxygen gradients throughout the depth of the scaffold (page 79, right col. paragraph 1; Figure 6). De la Puente teaches the 3DTEBM cultures allowed proliferation of MM cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche such as oxygen and drug gradients, and induced drug resistance in MM cells more than 2D or commercial 3D tissue culture systems (Abstract). One would have been motivated to combine the teachings of Gerner and de la Puente as Gerner teaches the presence of crosslinked fibrinogen in tumors and de la Puente teaches crosslinked fibrinogen supports cancer cell growth.
Regarding the combined teachings of Gerner, de la Puente, and Shiozawa, a POSITA would have been motivated to combine the teachings of Gerner, de la Puente, and Shiozawa in a 3D scaffold comprising peripheral blood plasma from one or more subjects having cancer to study bone metastases of solid tumors and evaluate tumor therapies as Gerner teaches altered fibrin turnover may be responsible for tumor-promoting effects by various means and de la Puente teaches there is an urgent need to develop a model that addresses the limitations of 2D culture systems to investigate biological mechanisms and drug resistance that are relevant and translatable to improved patient response and Shiozawa teaches a large proportion of solid tumor metastases are bone metastases that establish footholds in the bone marrow and Shiozawa teaches little is known about the postdissemination and niche engagement events activated by prostate cancer cells to coopt the HSC niche and Shiozawa teaches metastases represent the most common malignant tumors involving the skeleton where nearly 70% of prostate cancer and breast cancer patients and 15% - 30% of patients with lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney cancer have bone lesions. A POSITA would have a reasonable expectation of success in combining the teachings as Gerner teaches the presence of crosslinked fibrin in tissue samples from six different types of cancer and de la Puente teaches the 3DTEBM cultures allowed proliferation of cancer cells, recapitulated their interaction with the microenvironment, recreated 3D aspects observed in the bone marrow niche such as oxygen and drug gradients and Shiozawa teaches human prostate cancer cells directly compete with HSCs for occupancy of the HSC niche and the HSC niche serves as a direct target for prostate cancer during dissemination and plays a central role in bone metastases.
Applicant Argues: On page 14, paragraph 1, Applicant asserts the teachings of Ma and Demol make it more plausible using hindsight that oxygen matters in 3D cultures but they still do not provide a motivation to engineer the claimed scaffold or a reasonable expectation of success that doing so would yield the particular claimed ranges of pO2 in a way that faithfully recapitulates human solid-tumor drug responses.
Response to Arguments: This is not found persuasive Ma teaches culturing prostate cancer cells at 2 kPa (which is “about 2.5 kPa” of claim 36) and 20 kPa where the value of hypoxia affects the cellular and antigenic landscape of the cells (Abstract; page 3, left col. para. 2; page 4, right col. last para.; Figure 1; page 6, left col. para. 2 and right col. 1 – 3; page 9). Ma teaches by modifying the immune reactivity of prostate cancer cells in culture, manipulation of pO2 can be proposed as a new avenue for improving diagnosis, prognosis, and immunotherapy for prostate cancer (Abstract). Ma teaches prostate cancer is the second most common cancer in men worldwide and metastatic prostate cancer is not curable by surgery and is resistant to chemotherapy and ionizing radiation (page 1, left col.). Ma teaches similar to most solid tumors, prostate cancer tissues are characterized by low oxygen tension that is a marker of poor clinical prognosis (page 1, left col.). Ma teaches it has generally been accepted that microenvironmental hypoxia is among the reasons for resistance to treatment (page 1, right col.). Ma teaches changes in pO2 modulate innate and adaptive immunity (page 2, left col. para. 2). Ma teaches low pO2 is commonly associated with tumor aggressiveness (page 10, left col.).
Demol teaches a model of oxygen tensions throughout a fibrin scaffold comprising non-tumor cells where the fibrin scaffold was prepared with tranexamic acid (Abstract; page 109, right col. para. 4; Figure 2; page 116, left col. para. 2 – 4 and right col. para. 2; page 117, left col. para. 3). Demol teaches the model shows the oxygen tension ranging from anoxia to hypoxia to normoxia (0% to 21%) in the fibrin hydrogel with cells (Figure 5 – 9; page 113, right col. para. 2; page 114, left col. para. 1).
One would have been motivated to combine the teachings of Gerner, de la Puente, Shiozawa, Ma, and Demol in a scaffold with an oxygen gradient to study bone metastases of solid tumors and evaluate tumor therapies as Ma teaches prostate cancer is the second most common cancer in men worldwide and metastatic prostate cancer is not curable by surgery and is resistant to chemotherapy and ionizing radiation and Ma teaches similar to most solid tumors, prostate cancer tissues are characterized by low oxygen tension that is a marker of poor clinical prognosis. One would have a reasonable expectation of success in combining the teachings as Ma teaches culturing prostate cancer cells at 2 kPa and 20 kPa where the value of hypoxia affects the cellular and antigenic landscape of the cells and Ma teaches low pO2 is commonly associated with tumor aggressiveness and Demol teaches oxygen tension ranging from anoxia to hypoxia to normoxia (0% to 21%) in the fibrin hydrogel with cells.
A POSITA would know and Ma teaches that similar to most solid tumors, prostate cancer tissues are characterized by low oxygen tension that is a marker of poor clinical prognosis (page 1, left col.). Ma teaches it has generally been accepted that microenvironmental hypoxia is among the reasons for resistance to treatment (page 1, right col.).
Regarding Applicant’s assertion of hindsight, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant’s disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant Argues: On page 14, paragraph 3 – 5 and page 15, para. 1 – 2, Applicant asserts that Duong and Bahlis do not provide a coherent reason to modify Gerner, de la Puente, and Shiozawa to arrive at the claimed stiffness.
Response to Arguments: This is not found persuasive because Gerner teaches crosslinked fibrin in solid tumors known to have hypoxic regions and peripheral blood plasma of cancer patients and that cancer patients have abnormalities in coagulation parameters. De la Puente teaches the 3D scaffold structure of fibrin for cell culture is composed of a network of interconnected pores through which cells activity migrate, multiply and spread along the scaffold, the diffusion of nutrients and waste products is facilitated, and vascularization is promoted and developed (page 77, right col. paragraph 1). Therefore, the combined teachings of Gerner and de la Puente are cancer-related and the solid tumors of Gerner would be known to be hypoxic by a POSITA and a POSITA would know that different tumor types having crosslinked fibrin as taught by Gerner would differ in structure/stiffness and thus would adjust the stiffness of the crosslinked fibrin as taught by Duong where with stiffness values from about 0.5 kPa to 4.5 kPa depending on the concentration of fibrinogen and thrombin and cell seeding density (Figure 2; page 1868, left col. last paragraph; Figures 7 and 8).
Applicant Argues: On page 15, paragraph 3 – 5 and page 16, para. 1, Applicant asserts that Yayon does not involve tumor-patient peripheral blood plasma, does not discuss hypoxic culture conditions, and does not address in vitro tumor drug-response modeling and Yayon does not bridge the gap between the cited art and the specific limitations of claim 41.
Response to Arguments: This is not found persuasive because Yayon teaches a scaffold comprising cross-linked plasma obtained from a patient and the scaffold can comprise aprotinin, tranexamic acid, or epsilon-aminocaproic where plasma cross-linked matrix with pore diameters of 9, 10, 14, and 16 µm (Table 2; page 11, 0164; page 12, 0177; page 17, 0242 and 0244; Figure 1 and 7). Yayon teaches porous structures are useful for supporting cell growth in vitro (page 1, 0005). Yayon teaches fibrinogen is a major plasma protein and in the presence of calcium ions and thrombin forms a glue useful for tissue culture (page 1, 0009). Yayon teaches there remains an unmet need for a natural, three dimensional matrix that integrates a matrix having optimal pore size , pore distribution, and interconnected channels for cell maintenance and nutrient diffusion while it provides a structural support (page 1, 0024). One would have been motivated to combine the teachings of Gerner, de la Puente, Shiozawa, and Yayon in a scaffold with an oxygen gradient to study bone metastases of solid tumors and evaluate tumor therapies where cell growth is supported as Yayon teaches there remains an unmet need for a natural, three dimensional matrix that integrates a matrix having optimal pore size , pore distribution, and interconnected channels for cell maintenance and nutrient diffusion while it provides a structural support. One would have a reasonable expectation of success in combining the teachings as both de la Puente and Yayon teach the scaffold comprises fibrinogen and tranexamic acid and de la Puente teaches the 3D scaffold structure of fibrin for cell culture is composed of a network of interconnected pores through which cells activity migrate, multiply and spread along the scaffold, the diffusion of nutrients and waste products is facilitated, and vascularization is promoted and developed.
Applicant argues: On page 16, Applicant respectfully requests that the double patenting rejection be held in abeyance until the claims are otherwise in condition for allowance.
Response to Arguments: With respect to holding the rejection in abeyance, MPEP 804 states a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated.
The previous double patenting rejection has been withdrawn in view of Applicant’s amendment to the claims and a new rejection set forth above.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZANNA M BEHARRY whose telephone number is (571)270-0411. The examiner can normally be reached Monday - Friday 8:45 am - 5:45 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
Prosecution Insights