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 .
Status of Application
Claims 1-21 are under examination.
Specification
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
Claim Objections
Claim 11 is objected to because of the following informalities: “concentration of about 0.001-1.90 mg” is not a concentration. Appropriate correction is required.
Claim Interpretation
Claims 1-2 and 12 recite intended use “for preparing a technetium-99m (99mTc)-labeled composition”. The examiner interprets this to mean the composition must be capable of forming a 99mTc-labeled composition at some later point. The examiner notes that the rest of the claim does not fully set forth the embodiment of providing 99mTc, therefore this portion of the preamble is interpreted as providing “life, meaning, and vitality” to the claim. See MPEP 2111.02. For the purposes of examination, the examiner interprets any prior art with compositions for preparing a technetium-99m-labeled composition as reading on this limitation.
Claims 1-2 and 12 recite intended use “for targeting an injured site in a blood vessel”. In the case where preamble statements recite purpose or intended use, when the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. The examiner notes the remainder of the claim set fully sets forth limitations of the claimed invention. See MPEP 2111.02(II). Therefore, the examiner interprets “for targeting an injured site in a blood vessel” as non-limiting to claim 1-2 and 12.
Claim 11 recites a concentration of about 0.001-1.90 mg or 0.005-10 mM. The examiner notes that the specification recites the same “0.001-1.90 mg” as an amount of stannous chloride added (pg 16, para [0085]) and is not listed as a concentration. Therefore, for the purposes of examination, the examiner interprets, “concentration of about 0.001-1.90 mg or 0.005-10 mM” to mean an “amount of about 0.001-1.90 mg or a concentration of about 0.005-10 mM”. Any prior art reading on these amounts or concentrations, reads on this claim limitation.
Claim 12 recites the claim term “incubating” in line 8. The examiner notes that the specification does not define a time frame for “incubating”. The examiner further notes that the specification gives many timeframes for similar words of “incubation”, “incubated”, etc. but the specification is silent as to defining an upper or lower limit for timeframe for incubation. The specification lists times of 1 hr (pg 23, para [00114]), 20 min (pg24, para [00115]), 30 min (pg 28, para [00127]), 24 hours (pg 28, para [00127]), 0.5, 3, 6, and 24 hours (pg 28, para [00127]) and untimed (pg 3, para [0013]). For the purposes of examination, the examiner interprets the incubation time as any amount of time with no upper or lower limit and any prior art which has the components together for any amount of time, reads on this limitation.
Claim 17 recites a product by process. Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. See MPEP 2113(I). And the structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See MPEP 2113(II). The examiner notes, for the purposes of examination, that the product is a composition which can be the same as claim 12. Therefore, the examiner interprets any prior art reading on claim 12 reads on this claim.
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) 1-2, 7, 9, 12-14, and 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lungu, A.; et al., Evaluation of Fibrinogen-DTPA-99mTc Biodistribution and Imaging Studies, International symposium on modern trends in radiopharmaceuticals for diagnosis and therapy, 1998, 91-96 (as cited in the IDS filed on 10/11/2024).
Lungu, V.; et al. (hereafter referred to as Lungu) is drawn to labelling fibrinogen with 99mTc using DTPA chelator and studying venous thrombi through biodistribution and imaging methods (title; abstract). Lungu teaches early diagnosis of thrombosis and free moving thrombi can be achieved through labelling with different radionuclides (pg 91, para 1, lines 1-2) and that using chelators to label macromolecules such as fibrinogen with 99mTc has been studies (pg 91, para 1, lines 2-4). Lungu teaches a kit for preparing fibrinogen labeled with 99mTc (pg 91, lines 1-2) and methods of synthesis pg 93, para 3-5) and methods of labeling (pg 93, para 6, lines 1-4) and methods of purification through chromatography (pg 93, para 7, lines 1-8). Lungu teaches lyophilization of the fibrinogen chelator conjugate (pg 93, para 4, lines 1-5) and administration of the fibrinogen-DTPA-99mTc composition to rats for biodistribution studies (pg 94, para 1, lines 1-5) and to rabbits to image thrombi (pg 94, para 2, lines 1-4). Lungu teaches that fibrinogen-DTPA-99mTc has relatively fast and high uptake in the thrombi and that accumulation of the radioactivity in thrombi was at 60 minutes after injection and would be useful in imaging thrombosis (pg 94, para 3, lines 1-6) and that imaging of the thrombosis shows localization of the thrombi is possible (pg 94, para 4, lines 1-2; pg 95, Figure 3). Lungu teaches that fibrinogen-DTPA-Sn(II) kit for labelling with 99mTc can by lyophilizes, sterile, and pyrogen-free and is a promising clinical diagnostic agent for the detection of thrombi (pg 95, para 1, lines 1-4).
As to claim 1, Lungu teaches a kit for preparing a 99mTc-labeled composition (pg 91, para 2, lines 1-2) for targeting an injured site in a blood vessel (abstract, lines 1-4; pg 91, para 1, lines 1-4) comprising a human fibrinogen (pg 93, para 3, lines 1-3), a chelating agent, DTPA (abstract, line 1; pg 91, para 2, lines 1-3; pg 91, para 3, line 1; pg 93, para 3, lines 1-3) and a reducing agent (pg 93, lines 1-3).
Lungu does not expressly teach a single embodiment comprising all the features of the claimed product. However, it would be prima facie obvious prior to the effective filing date of the claimed invention to combine the embodiments of 99mTc-labeled composition for targeting an injured site in a blood vessel comprising a human fibrinogen, a chelating agent of DTPA, and a reducing agent taught by Lungu as a skilled artisan recognizes that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the combination of a kit containing 99mTc-labeled composition of human fibrinogen, DTPA, and a reducing agent.
As to claim 2, Lungu teaches a kit for preparing a 99mTc-labeled composition (pg 91, para 2, lines 1-2) for targeting an injured site in a blood vessel (abstract, lines 1-4; pg 91, para 1, lines 1-4) comprising a conjugated human fibrinogen wherein the human fibrinogen is bonded to a chelating agent, DTPA, (pg 93, par 3,lines 1-3; pg 93, para 4, line 4; pg 92, Figure 1) and a reducing agent (pg 93, lines 1-3).
As to claim 7, Lungu teaches a buffering compound, HEPES (pg 93, para 3, lines 1-2) which is lyophilized and included in the vial of the conjugated human fibrinogen (pg 93, para 5, lines 1-6).
As to claim 9, Lungu teaches the kit is provided as a lyophilized powder (pg 93, para 5, lines 2-7; pg 93, para 6, lines 1-2).
As to claim 12, Lungu teaches a method for preparing a 99mTc-labeled fibrinogen composition (pg 93, para 6, lines 1-4) comprising providing a conjugated human fibrinogen and reducing agent using a kit (abstract, line 9; pg 92, par 2, lines 1-2; pg 93, para 3, lines 1-3; pg 93, para 4, lines 1-3pg 93, para 5, lines 1-2). Lungu teaches providing a conjugated human fibrinogen with the 99mTc-containing solution (pg 93, para 6, lines 1-5) wherein the reducing agent is combined with the conjugated human fibrinogen before the 99mTc-containing solution is added (pg 93, para 4, lines 1-4), incubating the combined conjugated human fibrinogen, reducing agent, and 99mTc-containing solution to give the 99mTc-labeled fibrinogen composition (pg 93, para 6, lines 1-4).
As to claim 13, Lungu teaches the conjugated human fibrinogen is prepared as a solution (pg 93, para 3, lines 1-3) and the reducing agent is added to the solution before combination with the 99mTc-containing solution (pg 93, para 4, lines 1-3).
As to claim 14, Lungu teaches the 99mTc-containing solution is Na99mTcO4 solution (pg 93, para 6, lines 1-4).
As to claim 17, Lungu teaches a composition containing 99mTc-labeled fibrinogen with a reducing agent (pg 93, para 4, lines 1-3; pg 93, para 5, lines 1-6) and a method for preparing a 99mTc-labeled fibrinogen composition (pg 93, para 6, lines 1-4) comprising providing a conjugated human fibrinogen and reducing agent using a kit (abstract, line 9; pg 92, par 2, lines 1-2; pg 93, para 3, lines 1-3; pg 93, para 4, lines 1-3; pg 93, para 5, lines 1-2). Lungu teaches providing a conjugated human fibrinogen with the 99mTc-containing solution (pg 93, para 6, lines 1-5) wherein the reducing agent is combined with the conjugated human fibrinogen before the 99mTc-containing solution is added (pg 93, para 4, lines 1-4), incubating the combined conjugated human fibrinogen, reducing agent, and 99mTc-containing solution to give the 99mTc-labeld fibrinogen composition (pg 93, para 6, lines 1-4).
As to claim 18, Lungu teaches a method for detecting an internal bleeding stie in a subject (pg 94, para 2, lines 1-4) comprising administering the composition to the subject (pg 94, para 2, lines 2-3) and imaging a region of interest of the subject (pg 94, lines 3-4) where internal bleeding sites were detected in the subject (pg 94, para 3, line 6; pg 94, para 4, lines 1-2; pg 95, Figure 3).
Claim(s) 3-4, 15, 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lungu as applied to claims 1-2, 7, 9, 12-14, and 17-18 above, and further in view of Wong, D. W.; US 4,636,380. The teachings of Lungu as applied in the previous rejection are incorporated in this rejection.
As to claim 3, Lungu teaches the reducing agent is prepared from stannous chloride (pg 93, para 1, lines 2-3).
Lungu does not expressly teach the reducing agent is stannous chloride.
Wong, D. W. (hereafter referred to as Wong) is drawn to methods of labeling protein substances with indium radionuclides under physiological conditions for imaging of thrombi, emboli, myocardial infarcts, and tumors or vascular abnormalities in the body (title; abstract). Wong teaches radioiodinated antibodies are versatile, sensitive and accurate in clinical applications, technetium labeled proteins, such as 99mTc-labeled human serum albumin (HSA) or 131I-labeled HSA has been useful in imaging blood pooling (col 1, lines 29-35) and that radioiodinated human fibrinogen has offered clinicians more sensitivity of deep vein thrombosis but that there is a need for a better radiolabel more compatible gamma detection (col 1, lines 38-45) and that 99mTc-labeled human plasma proteins such as HAS, fibrinogen, antibodies or antibody fragments have all been successful with 99mTc-labeled HAS particularly useful in humans. Wong teaches that reducing agent used in the labeling of the proteins has a significant effect on physiobiological properties and can render the application unsuitable (col 2, lines 19-29) and that using stannous chloride works well (col 5, lines 43-47) and that reactions under physiological pH conditions help preserve the protein properties (col 2, lines 40-48). Wong teaches that chelators, such as DTPA and EDTA, are commonly used to radiolabel these plasma proteins (col 3, lines 35-48). Wong teaches methods of producing the radiolabeled proteins (col 6, lines 40-68).
Regarding stannous chloride reducing agent, Wong teaches stannous chloride as the reducing agent (col 11, lines 12-14; col 13, lines 22-28).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to substitute the reducing agent of Lungu with the reducing agent as taught by Wong because the substituted components and their functions were known in the art and a person of ordinary skill int eh art could have substituted one reducing agent for another, and the result of the substitution would have yielded the predictable outcome of stannous chloride as the reducing agent for the composition of Lungu.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the reducing agent of Lungu with the reducing agent of Wong because the prior art of Lungu disclosed stannous chloride as the precursor of the reducing agent known to aid in labeling (pg 93, para 1 lines 1-5) and additional prior art of Wong suggested that preparation of radiolabeled protein stannous chloride works (col 7, lines 1-3; col 14, lines 1-4) due to the overlap in the requirements of reducing agents between them involves known reduction of the radioisotope for chelation. The skilled artisan would have been motivated to make the substitution because stannous chloride under mild conditions is preferred to the sodium hydroxide method of Lungu.
As to claim 4, Lungu teaches a kit containing the DTPA conjugated human fibrinogen in vials (pg 92, para 5, lines 1-6; pg 92, para 6, line 1).
Lungu does not teach the stannous chloride in a second vial.
Wong teaches human fibrinogen in one vial and stannous chloride in a second vial (col 13, lines 22-28).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to modify the kit of Lungu to include the multiple vials as taught by Wong because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of vials for the DTPA conjugated human fibrinogen and stannous chloride.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the kit to have separate vials for the conjugated human fibrinogen and the stannous chloride because the prior art of Lungu disclosed that conjugated human fibrinogen can be combined with the reducing agent after conjugation (pg 93, para 4, lines 1-3) and that the kit can be stored in vials (pg 93, para 6, line 1-2). Additional prior art of Wong suggested that placing the human fibrinogen and stannous chloride in separate vials and then combining them has similar effect of producing the appropriate composition (col 13, lines 23-47) because of the overlap of the type of steps performed. The skilled artisan would have been motivated to place the stannous chloride in a separate vial from the conjugated human fibrinogen because to enable flexibility as to when the addition of the reducing agent is added relative to the radioisotope because keeping it separate enables adding the reducing agent before, at the same time, or after the radioisotope.
As to claim 15, Lungu teaches that a Sn-based reducing agent.
Lungu does not teach the stannous chloride as the reducing agent.
Wong teaches stannous chloride as the reducing agent (col 13, lines 22-28).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to modify the kit of Lungu to include the multiple vials as taught by Wong because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of vials for the DTPA conjugated human fibrinogen and stannous chloride.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the kit to have separate vials for the conjugated human fibrinogen and the stannous chloride because the prior art of Lungu disclosed that conjugated human fibrinogen can be combined with the reducing agent after conjugation (pg 93, para 4, lines 1-3) and that the kit can be stored in vials (pg 93, para 6, line 1-2). Additional prior art of Wong suggested that placing the human fibrinogen and stannous chloride in separate vials and then combining them has similar effect of producing the appropriate composition (col 13, lines 23-47) because of the overlap of the type of steps performed. The skilled artisan would have been motivated to place the stannous chloride in a separate vial from the conjugated human fibrinogen because to enable flexibility as to when the addition of the reducing agent is added relative to the radioisotope because keeping it separate enables adding the reducing agent before, at the same time, or after the radioisotope.
As to claim 21, Wong teaches internal bleeding site has inactive bleeding (col 10, lines 4-10).
Claim(s) 5-6 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lungu as applied to claims 1-2, 7, 9, 12-14, and 17-18 above, and further in view of Brechbiel, M. W.; et al. Synthesis of 1-(p-isothiocyanatobenzyl) Derivatives of DTPA and EDTA. Antibody Labeling and Tumor-Imaging Studies, Inorg. Chem., 1986, 25, 2772-2781. The teachings of Lungu as applied in the previous rejections are incorporated in this rejection.
As to claim 5, Lungu teaches the chelating agent is DTPA.
Lungu does not teach the chelating agent is p-SCN-Bz-DTPA.
Brechbiel, M. W.; et al. (hereafter referred to as Brechbiel) is drawn to radiolabeling of tumor-localizing monoclonal antibodies with a derivative of DPTA and EDTA (title; abstract). Brechbiel teaches that radioisotope labeling of proteins is sought due to the ability to inject the radiolabeled proteins and image the target tissues (pg 2772, col 1, para 1, lines 1-5) and that the choice of the chelator if important (pg 2772, col 1, para 3, lines 1-3) and that DTPA and EDTA derivatives are common but covalent linkage to the protein is inefficient and requires extensive purification before labeling with radionuclides (pg 2772, col 1, para 3, lines 4-9). Brechbiel teaches a p-SCN-Bz derivative of DTPA and EDTA which reacts rapidly and efficiently with antibodies and retains the metal for a long time compared to the radiometals half-life (pg 2772, col 1, para 4, lines 1-4; pg 2772, Chart I) and that the p-SCN-Bz-DTPA chelator performed well in comparison to the DTPA for providing tissue images free of extraneous background (pg 2773, col 2, para 2, lines 11-13; pg 2778, Figures 1-2). Brechbiel teaches the synthesis of the chelator (pg 2775, col 2, para 4, lines 1-8) and coupling the chelators to antibodies (pg 2775, col 2, para 8-10; pg 2779, Table 1).
Regarding the chelating agent p-SCN-Bz-DTPA, Brechbiel teaches p-SCN-Bz-DTPA (pg 2772, col 1, para 4, lines 1-4; pg 2772, Chart I; pg 2773, col 2, para 2, lines 11-13; pg 2778, Figures 1-2).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to substitute DTPA of Lungu with the p-SCN-Bz-DTPA as taught by Brechbiel because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of the composition of Lungu with the chelator of Brechbiel.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the DTPA of Lungu with the p-SCN-Bz-DTPA of Brechbiel because the prior art of Lungu disclosed the DTPA chelator was known to chelate radiometal, 99mTc. Additional prior art of Brechbiel suggested that DTPA and p-SCN-Bz-DTPA have similar chelating and imaging properties because of the overlap of the DTPA and DTPA portion of the p-SCN-Bz-DTPA (pg 2773, col 2, para 2, lines 11-13; pg 2778, Figures 1-2). The skilled artisan would have been motivated to substituting DTPA with p-SCN-Bz-DTPA because the thiocyanate functional group enables rapid and efficient coupling with antibodies compared to DTPA and still maintains good imaging properties.
As to claim 6, Brechbiel teaches molar ratios of the chelating agent to the protein is from 0.5:1 to 8:1 (pg 2779, Table 1). This range overlaps with the prior art range of 1:1 to 30:1. In such cases where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.
As to claim 16, Lungu teaches DTPA (pg 93, para 3, lines 1-3).
Lungu does not teach p-SCN-Bz-DTPA.
Brechbiel teaches p-SCN-Bz-DTPA (pg 2772, col 1, para 4, lines 1-4; pg 2772, Chart I; pg 2773, col 2, para 2, lines 11-13; pg 2778, Figures 1-2).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to substitute DTPA of Lungu with the p-SCN-Bz-DTPA as taught by Brechbiel because the substituted components and their functions were known in the art and a person of ordinary skil int eh art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of the composition of Lungu with the chelator of Brechbiel.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the DTPA of Lungu with the p-SCN-Bz-DTPA of Brechbiel because the prior art of Lungu disclosed the DTPA chelator was known to chelate radiometal, 99mTc. Additional prior art of Brechbiel suggested that DTPA and p-SCN-Bz-DTPA have similar chelating and imaging properties because of the overlap of the DTPA and DTPA portion of the p-SCN-Bz-DTPA (pg 2773, col 2, para 2, lines 11-13; pg 2778, Figures 1-2). The skilled artisan would have been motivated to substituting DTPA with p-SCN-Bz-DTPA because the thiocyanate functional group enables rapid and efficient coupling with antibodies compared to DTPA and still maintains good imaging properties.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lungu as applied to claims 1-2, 7, 9, 12-14, and 17-18 above, and further in view of Rhodes, B. A.; U.S. 4,305,922. The teachings of Lungu as applied in the previous rejections are incorporated in this rejection.
As to claim 8, Lungu teaches purification by chromatography (pg 93, para 7, lines 1-2).
Lungu does not teach a purification column.
Rhodes, B. A. (hereafter referred to as Rhodes) is drawn to labeling proteins with 99mTc and purifying the system with columns (title; abstract). Rhodes teaches a method of labeling proteins with 99mTc through ligand exchange (col 1, lines 61-68) and teaches a ligand exchange procedure (col 3, lines 2-40) and administering the labeled protein by intravenous injection in a pharmaceutically acceptable saline solution, sterile and pyrogen-free (col 3, liens 61-63) and determining the tumor locations (col 4, lines 1-4). Rhodes teaches human serum albumin labeling (col 4, lines 37-64) and human fibrinogen (col 5, lines 40-62).
Regarding purification columns, Rhodes teaches purification columns (abstract, lines 6-14; col 3, lines 9-17; col 5, lines 50-57).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to modify the kit of Lung to a purification column as taught by Rhodes because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a kit with a purification column.
A person of ordinary skill in the art would have had a reasonable expectation of success in including a purification column in the kit because the prior art of Lungu disclosed a purification method known for radiochemical purification through chromatography and solvents (Lungu, pg 93, para 7, lines 1-3). Additional prior art of Rhodes suggested column chromatography as a means to achieve similar behavior of radiochemical purification (Rhodes, col 5, lines 44-56). The skilled artisan would have been motivated to include a purification column in the kit because the radioisotope has a half-life and it can be helpful to remove the half-life induced impurities from the radioisotope before using in a clinical setting.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lungu as applied to claims 1-2, 7, 9, 12-14, and 17-18 above, and further in view of Schulz, P. M.; et al. Biochemical characterization, stability, and pathogen safety of a new fibrinogen concentrate (fibryga®), Biologicals, 2018, 52, 72-77 (as cited in the IDS filed on 10/11/2024). The teachings of Lungu as applied in the previous rejections are incorporated in this rejection.
As to claim 10, Lungu teaches human fibrinogen (pg 93, para 1, lines 3-5).
Lungu does not teach the amount of albumin present in the fibrinogen.
Schulz, P. M.; et al. (hereafter referred to as Schulz) is drawn to the characterization, stability, and safety of a fibrinogen concentrate for intravenous use (title; abstract). Schulz teaches that fibrinogen is known as clotting factor I and is critical in clot formation (pg 72, col 1, para 1, lines 1-2) and that fibrinogen consists of two sets of three subunits linked via disulfide bridges forming a rod-shaped molecules with a molecular weight of 340 kDa (pg 72, col 1, para 2, lines 1-6) and that low levels of fibrinogen are associated with increased risk of bleeding (pg 72, col 1, para 2, lines 4-5) and that administration of fibrinogen as a therapy is used in several countries (pg 72, col 2, para 2, lines 1-9). Schulz teaches that fibrinogen concentrate can be highly purified and made safe for use in vivo (pg 72, col 2, para 3, lines 1-3) and the fibrinogen can be lyophilized for convenient usage and functionality of the target protein with high purity and high pathogen safety for effective treatment of fibrinogen deficiency (pg 73, col 1, para 2, lines 3-9). Schulz teaches the manufacturing of fibrinogen concentrate (pg 73, col 1, para 7, lines 1-12) and the characterization of the fibrinogen (pg 74, Table 1). Schulz teaches even high purity fibrinogen for use in in vivo applications contains albumin (pg 74, Table 1; pg 75, Figure 2).
Regarding albumin amounts in fibrinogen, Schulz teaches that fibrinogen has albumin 0.01-0.03% (w/w) (pg 74, Table 1). The claimed range of 0.01-40% (w/w) overlaps with this range. In such cases where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to modify the composition of Lungu to include amounts of albumin as taught by Shulz because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of amounts of albumin in the fibrinogen.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the composition of fibrinogen of Lungu to include the amounts of albumin because the prior art of Lungu disclosed that the fibrinogen used was known to be obtained in reagent grade (pg 93, para 2, line 1) and was obtained in a lyophilized form (pg 93, para 1, lines 1-5). Additional prior art of Schulz suggested lyophilized fibrinogen concentrate contains amounts of albumin among other proteins (pg 74, Table 1). Because of the overlap between the lyophilized forms of fibrinogen and that even fibrinogen obtained for human use has albumin in it, it would have been prima facie obvious to include the albumin content in Lungu. The skilled artisan would have been motivated to include the amount of albumin in the fibrinogen because using compounds in humans requires accurate reporting of all compounds, proteins, excipients, etc. in the composition and reporting the amount of albumin included would be necessary for application.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lungu as applied to claims 1-2, 7, 9, 12-14, and 17-18 above, and further in view of Layne, W. W.; et al. Evaluation of the Viability of In-111-Labeled DTPA Coupled to Fibinogen, J. Nucl. Med., 1982, 23, 627-630. The teachings of Lungu as applied in the previous rejections are incorporated in this rejection.
As to claim 11, Wong teaches fibrinogen is provided in an amount of 0.1-100 mg (col 13, lines 41-47), stannous chloride is provided in an amount of 0.1-5 mg (col 13, lines 22-24).
Wong does not teach the chelating agent in an amount of 0.1-5 µg.
Layne, W. W.; et al. (hereafter referred to as Layne) is drawn to evaluation of the viability of In-111-labeled DTPA conjugated to fibrinogen with various molar ratios and evaluation of the effect after administration on the imaging (title; abstract). Layne teaches methods for the preparation of proteins to which strong chelating groups are covalently attached (pg 627, col 1, liens 1-3) and particularly DTPA as the chelator (pg 627, col 2, para 2, lines 1-7) and coupled to fibrinogen (pg 628, col 1, para 1, lines 2-4) and methods of compound the chelator to the fibrinogen (pg 627, col 2, para 3, lines 1-3; pg 628, col 1, para 1, lines 1-6) and labeling with a radioisotope (pg 628, col 1, para 3, lines 1-6). Layne teaches in vivo studies (pg 628, col 2, para 3, lines 1-10).
Regarding the scale of the amounts of fibrinogen and chelating agent, Layne teaches about 21-105 µg of chelating agent (pg 627, col 2, para 3, lines 1-3). In the case where ranges are close, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). Additionally, mere scaling up of a prior art process capable of being scaled up, if such were the case, would not establish patentability in a claim to an old process so scaled. See MPEP 2144.04(IV)(A).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to modify the amounts of fibrinogen and reducing agent of Wong to include the amounts chelating agent as taught by Layne because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the fibrinogen, chelating agent, and reducing agent.
A person of ordinary skill in the art would have had a reasonable expectation of success in combining the protein and reducing agent of Wong with the chelating agent because the prior art of Wong taught a method for preparing radiolabeled proteins where the protein and stannous chloride were present in the appropriate amounts and the additional prior art of Layne suggested that radiolabeling of proteins were the DTPA chelator was present in the appropriate amount would result in similar compound because of the overlap of the fibrinogen structure. The skilled artisan would have been motivated to use the chelator in the amount claimed with the fibrinogen and stannous chloride in the kit because the mole ratio of chelator to fibrinogen that this weight ratio enables works for radiolabeled fibrinogen (Layne, pg 627, col 2, para 3, lines 1-3).
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lungu as applied to claims 1-2, 7, 9, 12-14, and 17-18 above, and further in view of Price, E. W.; et al. Matching chelators to radiometals for radiopharmaceuticals, Chem. Soc. Rev., 2014, 43, 260. The teachings of Lungu as applied in the previous rejections are incorporated in this rejection.
As to claim 19, Lungu teaches a method wherein imaging is conducted using a PhoGamma camera (pg 94, para 2, lines 3-4).
Lungu does not expressly teach SPECT.
Price, E. W.; et al. (hereafter referred to as Price) is drawn to matching chelators to radiometals for radiopharmaceuticals for use in diagnostic imaging techniques such as SPEC, PET, and for therapeutic applications (title; abstract). Price teaches that radiometal ions must be sequestered from aqueous solution using chelators to obviate trans-chelation and hydrolysis (pg 260, col 1, para 1, lines 1-6) and that 99mTc is a great radiometal for SPECT and that 67Ga, 111In, 177Lu can all be used with SPECT for imaging in chelator-based radiopharmaceuticals as well. Price teaches that chelators can be covalently conjugated to peptides, nucleotides, antibodies, and nanoparticles (pg 261, col 1, para 2, lines 1-5) and that a variety of functional groups can be used to link the chelator to the peptides, etc such as carboxylic acids, activated esters, isothiocyanes and maleimides (pg 261, para 2, lines 6-10; pg 263, Figure 1). Price teaches that matching of chelators and radiometals can be done to enable radiolabeling in high yields, and determine the conditions necessary (pg 263, col 2, para 3, lines 1-8) and Price teaches a variety of derivatives of common chelators that can be substituted with each other, such as DOTA and its derivatives (pg 267, Table 2), TETA and its derivatives (pg 270, Table 4), NOTA and its derivatives (pg 272, Table 6), DTPA and its derivatives (pg 274, Table 7), HBED and its derivatives (pg 278, Table 10).
Regarding SPECT, Price teaches (abstract, line 3; pg 260, col 2, par 1, lines 3-6; pg 261, col 2, para 2, lines 7-14).
It would have been prima facie obvious to a person of ordinary skill in the art before the
effective filing date to substitute the imaging method of Lungu with the imaging method as taught by Price because the substituted components of a Pho Gamma scintogram method and the SPECT method and their functions were known in the art and a person of ordinary skill in the art could have substituted one known imaging method for another, and the results of the substitution would have yielded the predictable result of a method of imaging using SPECT.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the scintogram method of Lungu with the SPECT method of Price because the prior art of Lungu teaches that scintigraphy works with 99mTc radioisotopes (Lungu, pg 94, para 2, lines 3-4) and the additional prior art of Price disclosed that SPECT can be used with 99mTc radioisotopes (pg 260, col 2, par 1, lines 3-6) because of the overlap of the emission of the radioisotopes and the overlap in the imaging type where SPECT is a type of scintigraphy (pg 277, col 2, para 3, lines 9-10). The skilled artisan would have been motivated substitute SPECT with scintigraphy because SPECT enables a 3D visualization of the subject whereas the gamma pho imaging is 2D.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lungu as applied to claims 1-2, 7, 9, 12-14, and 17-18 above, and further in view of Ohnishi, S.; et al. Radiolabeled and Near-Infrared Fluorescent Fibrinogen Derivatives Create a System for the Identification and Repair of Obscure Gastrointestinal Bleeding, Surgery, 2006, 140, 5, 785-792 (as cited in the IDS filed on 7/9/2026). The teachings of Lungu as applied in the previous rejections are incorporated in this rejection.
As to claim 20, Lungu teaches that a method for imaging a region of interest (pg 94, Table 1).
Lungu does not expressly teach the region of interest is within the gastrointestinal system of the subject.
Ohnishi, S.; et al. (hereafter referred to as Ohnishi) is drawn to radiolabeled and near-infrared fluorescent fibrinogen derivatives for the identification and repair of obscure gastrointestinal bleeding (title; abstract). Ohnishi teaches gastrointestinal bleeding is a common disorder and significant source of morbidity and mortality but that determining the site of bleeding is often difficult (pg 2, para 1, lines 1-3). Ohnishi teaches that injury to blood vessel wall triggers blood coagulation where fibrinogen aids in blood clotting therefore radiolabeling fibrinogen is a way to image vascular thrombus (pg 2, para 2, lines 1-5). Ohnishi teaches that adding a radioactive gamma-ray emitter or light-based fluorescence emitter might permit detection of the bleeding sites long after bleeding has stopped (pg 2, para 3, lines 1-4). Ohnishi teaches preparation of fluorescence labeled fibrinogen (pg 2, para 5, lines 1-5) and purification (pg 3, para 1, lines 1-12). Ohnishi teaches administration of the radiolabeled or fluorescence labeled fibrinogen (pg 4, para 3, lines 1-6) and imaging with a NIR fluorescence imaging system (pg 4, para 4, lines 1-5) and geiger counter (pg 4, para 5, lines 3-5). Ohnishi teaches that fluorescence labeled and radiolabeled fibrinogen can be used to detect the site of bleeding (pg 6, para 3, lines 1-8).
Regarding the region of interest is within the gastrointestinal system of the subject, Ohnishi teaches that the region of interest is within the gastrointestinal system of the subject (title; abstract; pg 2, para 1, lines 1-3; pg 2, para 3, lines 1-6; pg 5, para 4, lines 1-2).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Lungu to include imaging the gastrointestinal system as taught by Ohnishi because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of the method of imaging the gastrointestinal system of the subject.
A person of ordinary skill in the art would have had a reasonable expectation of success in having a region of interest be the gastrointestinal system because the prior art of Lungu disclosed a radiolabeled fibrinogen known to enable idntification of thrombi in organs (pg 94, para 3, lines 1-6, pg 94, Table 1). Additiaonl prior art of Ohnishi suggested to have radiolabeled fibrinogen known to have the similar properties of enabling identification of thrombi in another organ, the gastrointestinal system (pg 5, para 4, lines 1-2). The overlap of radiolabeled fibrinogen and detection using emission from the radioisotope involves known detection methods. The skilled artisan would have been motivated to have the gastrointestinal system as a region of interest because hemorrhages in the gastrointestinal system are often difficult to locate despite being a common disorder and a significant source of morbidity and mortality.
Pertinent Art
The prior art of Wong, D. W.; US 4,293,537 (as cited in the IDS filed on 10/11/2024) is deemed pertinent to the application.
Wong, D. W. (hereafter referred to as Wong 1981) is drawn to methods of labeling exogenous and autologous plasma proteins with technetium producing radioactive tracers (title; abstract). Wong 1981 teaches pulmonary embolism is the most preventable cause of death in hospitalized patients and that early detection of venous thrombosis would enable prompt anticoagulant therapy (col 1, lines 6-10) and that radiolabeled fibrinogen is useful for monitoring deep vein thrombi sensitive to hematoma and inflammatory exudate (col 1, lines 26-36). Wong 1981 teaches that 99mTc labeling is preferred to 131I labeling due to reduction of undesirable properties (col 2, lines 6-10) and that 99mTc is a pure gamma emitter (col 2, lines 10-11) and is safe in radiopharmaceuticals at higher doses (col 2, lines 12-18). Wong 1981 teaches a method of labeling human plasma proteins with 99mTc under physiological pH (col 4, lines 1-5) in the presence of stannous chloride (col 4, lines 9-11) and a method of making (col 7, lines 25-58) and a kit (col 7, lines 13-20), and methods for lyophilizing (col 8, lines 15-25).
The examiner considers the overlap in composition comprising a technetium labeled fibrinogen and methods of making and storing to render this art pertinent to this application.
The prior art of Yen, R. C. K.; US 2002/0142046 A1 (as cited in the IDS filed on 10/11/2024) is deemed pertinent to the application.
Yen, R. C. K. (hereafter referred to as Yen) is drawn to fibrinogen particles with stabilizing agents, reducing agents, oxidizing agents, hydrogen accepting molecules, polymers and sulfur-containing rings (title; abstract). Yen teaches that stable porous and membrane-less carriers delivering biological agents to sites within the body are advantageous and can be done through liposomes and microspheres (pg 1, para [0007]). Yen teaches protein particles can also be useful in encapsulation and delivery of nutrients and biologics (pg 1, para [0010], lines 1-3). Yen teaches protein particles in the nanometer and micrometer size range, suspended in aqueous medium, can be stable through additional materials such as reducing agents (pg 2, para [0020], lines 1-13). Yen teaches that fibrinogen coated particles administered intravenously can decrease bleeding time in patients and animals (pg 3, para [0024], lines 1-4). Yen teaches methods of preparing various antigens, including human fibrinogen (pg 7, para [0083]-[0086]) and with albumin (pg 11, para [0196], lines 1-4; pg 11, para [0197], lines 6-8). Yen teaches that stannous chloride can be used (pg 14, para [0291], lines 1-4), lyophilization of the particles (pg 14, para [0292, lines 1-4) and labeling with technetium and a chelator is useful (pg 14, para [0289], lines 1-7).
The examiner considers the overlap in composition comprising a technetium labeled fibrinogen through a chelator to render this art pertinent to this application.
Conclusion
No claims allowed.
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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