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 .
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.
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 2/23/2026 is acknowledged. The traversal is on the ground(s) that “the special technical feature of using a specific concentration 0.5-5.0 μg/ml of a secondary antibody for detecting AKRIC3 levels in various solid tumors...The special technical feature common to the instant claims makes a clear contribution over the prior art in view of Azzarello” (page 18 para. 1), “Without any guidance from the prior art, those skilled in the art could not readily obtain the concentration of the secondary antibody as required by the instant claims. Therefore, the above common technical feature is not obvious in view of Azzarello” (page 19 para. 1). This is not found persuasive because, over the course of prosecution, new art was found that teach the common technical feature, thus, breaking unity.
Groups I-II lack unity of invention because even though the inventions of these groups require the technical feature of a 0.5~5.0 µg/ml concentration of AKR1C3 monoclonal antibody solution and a 0.5~5.0 µg/ml concentration of secondary antibody solution, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Ashley et al. Urology Volume 76, Issue 1, July 2010, Pages 67-72 https://doi.org/10.1016/j.urology.2009.09.046 ("Ashley") in view of R&D Systems "Human Aldo-keto Reductase 1C3/AKR1C3 Antibody Monoclonal Mouse IgG1 Clone # 871701 Catalog Number: MAB7678" Rev. 2/7/2018-Cite No. A of IDS 2/7/2024 ("R&D") as evidenced by Vector Laboratories “Horse Anti-Mouse IgG Antibody (H+L), Biotinylated” (retrieved online https://vectorlabs.com/products/biotinylated-horse-anti-mouse-igg/?srsltid=AfmBOoqN63G6O0ct6zEZrprN8RHR-wMc5rLlcs9kMotM75wc2cViYwEp on 4/7/2026).
Ashley teaches “(AKR1C3) expression in surgically-removed cryptorchid testes” (Abstract). Ashley further suggests an AKR1C3 detection method, wherein AKR1C3 expression levels in isolated formalin-fixed paraffin-embedded human tissue specimen is detected by using immunohistochemical staining method (page 68 col. 1 para. 3, page 68 col. 1 para. 4), comprising the following steps: a) an antigen retrieval step comprising performing antigen retrieval by heating the formalin-fixed paraffin-embedded human tissue specimen at 90 to 115°C for 17 to 30 min in the presence of an antigen retrieval solution (page 68 col. 1 para. 4), b) a primary antibody incubation step comprising mixing the antigen-retrieved formalin-fixed paraffin-embedded human tissue specimen with AKR1C3 monoclonal antibody solution for incubation for 25 to 700 min (“Slides were incubated with monospecific mouse anti-AKR1C3 monoclonal antibody, NP6G6.A6,10 diluted 1:200 in TBS with 1% BSA...Following primary antibody incubation at 4°C overnight, the sections were rinsed with TBS” page 68 col. 1 para. 4). Ashley further suggests c) a secondary antibody incubation step comprising mixing the primary antibody-incubated formalin-fixed paraffin-embedded human tissue specimen with a 0.5 to 5.0 µg/ml concentration of secondary antibody solution and incubating for 25 to 700 min (“Biotinylated horse anti-mouse secondary antibody, diluted to 1:400 (Vector Laboratories, Inc., Burlingame, CA) with TBS and 1% BSA, was applied and incubated for 2 hours at room temperature” page 68 col. 1 para. 4). Note that the secondary antibody taught by Ashley, the biotinylated horse anti-mouse from Vector Laboratories, has a concentration of “1.5 mg active conjugate/ml” (page 4 of Vector Laboratories). Therefore, the 1:400 dilution of the secondary antibody taught by Ashley corresponds to 3.75 μg/ml concentration. Ashley further teaches that “[u]sing the cryptorchid testis as a developmental model, one can study when the enzyme is expressed, where it is localized, and propose theories for why its presence is required. The goal of our study was to characterize AKR1C3 expression in surgically-removed cryptorchid testes” (page 67 col. 2 para. 2 and page 68 col. 1 para. 1).
Ashley fails to teach a primary AKR1C3 monoclonal antibody solution concentration of 0.5~5.0 µg/ml.
R&D teaches “Human Aldo-keto Reductase 1C3/AKR1C3 Antibody” (Title). R&D further teaches a 0.5 to 5.0 μg/ml concentration of AKR1C3 monoclonal antibody solution (“1-25 µg/mL” APPLICATIONS Immunohistochemistry page 1). R&D “recommends” a 0.5 to 5.0 μg/ml concentration of AKR1C3 monoclonal antibody solution for “immunohistochemistry” (“Recommended Concentration” APPLICATIONS Immunohistochemistry page 1). R&D further teaches that a “1.7 µg/mL” concentration enables the localization of “ Specific staining…localized to cytoplasm in epithelial cells” (DATA Immunohistochemistry page 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Ashley to rely on the 1.7 µg/mL concentration of primary monoclonal antibody taught by R&D because R&D teaches this is a recommended concentration for immunohistochemistry applications and enables the localization of AKR1C3 inside the cytoplasm in epithelial cells and Ashley is interested in immunohistochemistry of AKR1C3 and its localization. A person having ordinary skill in the art would have had a reasonable expectation of success because both Ashley and R&D teach monoclonal AKR1C3 antibodies for immunohistochemistry.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/CN2021/114774, filed 08/26/2021. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. CN202010911697.3, filed on 09/02/2020 in China.
Information Disclosure Statement
The information disclosure statements filed on 3/1/2023, 2/27/2024, 12/10/2024 and 10/1/2025 are being considered by the examiner.
Claim Objections
Claims 1 and 11-13 are objected to because of the following informalities:
In claim 1 lines 1-3, “wherein the AKR1C3 expression levels in isolated formalin-fixed paraffin-embedded human tissue specimen is detected by using immunohistochemical staining method" appears to be a typographical error, namely it is suggested that "wherein the AKR1C3 expression levels in isolated formalin-fixed paraffin-embedded human tissue specimen is detected by using immunohistochemical staining method" read as "wherein the AKR1C3 expression levels in an isolated formalin-fixed paraffin-embedded human tissue specimen is detected by using an immunohistochemical staining method" (emphasis added).
In claim 11 line 2, “wherein after the secondary antibody incubation of step c), further comprising:” appears to be a typographical error, namely it is suggested that “wherein after the secondary antibody incubation of step c), further comprising:” read as “wherein after the secondary antibody incubation of step c), the method further comprises:
In claim 12 lines 1-2, “wherein before the antigen retrieval of step a), further comprising:” appears to be a typographical error, namely it is suggested that “wherein before the antigen retrieval of step a), further comprising:” read as “wherein before the antigen retrieval of step a), the method further comprises:
In claim 13 lines 1-3, “wherein between the antigen retrieval of step a) and the primary antibody incubation of step b), further comprising:”, appears to be a typographical error, namely it is suggested that “wherein between the antigen retrieval of step a) and the primary antibody incubation of step b), further comprising:” read as “wherein between the antigen retrieval of step a) and the primary antibody incubation of step b), the method further comprises: .
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5-6, 8 and 10-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 and its dependent claims require an “AKR1C3 monoclonal antibody solution” that specifically binds to AKR1C3.
The specification does not describe which amino acid residues, or other molecular components are present in the genus of solutions encompassed by claims 1-2, 5-6, 8 and 10-14. The specification fails to disclose the structures common to all members of the genus and fails to provide sufficient specific examples of agents to be used. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
Regarding the claimed scope that includes antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies and variants, fragments or derivates of the antibodies of the claims.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the full genus of antibodies encompassed by the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of encompassed antibodies.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of each genus of claimed agents, i.e., AKR1C3 monoclonal antibodies (claims 1-2, 5-6, 8 and 10-14) and mouse monoclonal anti-AKR1C3 antibodies (claim 10). Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 5-6, 8 and 10-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “An AKR1C3 detection method, wherein the AKR1C3 expression levels in isolated formalin-fixed paraffin-embedded human tissue specimen is detected by using immunohistochemical staining method, comprising the following steps:…”. However, the limitation "the AKR1C3 expression levels" in line 1 is unclear. There is insufficient antecedent basis for this limitation in the claim. It is not clear which AKR1C3 expression levels are being claimed because AKR1C3 expression levels was not previously recited in claim 1.
Claim 1 further recites “a) antigen retrieval performing antigen retrieval by…b) primary antibody incubation mixing the…c) secondary antibody incubation mixing the…”. The limitations “a) antigen retrieval performing antigen retrieval by…b) primary antibody incubation mixing the…c) secondary antibody incubation mixing the” are unclear. These limitations may be interpreted in multiple ways. For example, these limitations appear to be a type of subheading, which is not proper. These limitations may also be interpreted to be typographical errors since they repeat the same limitation (as in step a)). Furthermore, “incubation mixing” is not clear because these are two different steps. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claim 1 further recites “90~115°C for 17~30 min…0.5~5.0 µg/ml…25~700 min…0.5~5.0 µg/ml…25~700 min”. These limitations are unclear. These limitations can be interpreted in multiple ways. For example, it is not clear if these are meant to be ranges or one approximate value. Furthermore, the limitation “~” is indefinite given that the specification fails to clearly define how much this approximation symbol encompasses. A person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim.
Claim 1 is also considered vague because it appears incomplete. Given that the claim recites method steps, there should be an “and” after step b) and before step c) to signify that the claim comprises three steps (a), b) and c)). Given this deficiency in the claim, a person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim.
Claim 2 recites “wherein in the antigen retrieval of step a), the antigen retrieval solution has a pH of 2.0 ~ 9.0; and/or more preferably, the antigen retrieval solution has a pH of 6.0 ~ 9.0; even more preferably, the antigen retrieval solution has a pH of 6.0, wherein in the antigen retrieval of step a), the antigen retrieval solution includes sodium citrate antigen retrieval solution or EDTA antigen retrieval solution; and/or wherein in the antigen retrieval of step a), the formalin-fixed paraffin-embedded human tissue specimen is heated at 92~102 °C for 18~25 min”. The limitations “pH of 2.0 ~ 9.0… pH of 6.0 ~ 9.0…92~102 °C for 18~25 min” are unclear, similar to claim 1. It is not clear if these are meant to be ranges or one approximate value. Furthermore, the limitation “~” is indefinite given that the specification fails to clearly define how much this approximation symbol encompasses. Also, the phrases “more preferably”, “even more preferably” render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). A person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim.
Claim 5 recites “wherein in the primary antibody incubation of step b), the AKR1C3 monoclonal antibody solution has a concentration of 1.0~3.0 μg/ml; more preferably, the AKRIC3 monoclonal antibody solution has a concentration of 1.2 μg /ml; and/or, in the secondary antibody incubation of step c), the secondary antibody solution has a concentration of 1.0~3.0 μg/ml; more preferably, the secondary antibody solution has a concentration of 1.2 μg/ml”. The limitations “1.0~3.0 μg/ml … 1.0~3.0 μg/ml” are unclear. It is not clear if these are meant to be ranges or one approximate value. Furthermore, the limitation “~” is indefinite given that the specification fails to clearly define how much this approximation symbol encompasses. Also, the phrases “more preferably” render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention.
Claim 6 recites “wherein the AKRIC3 monoclonal antibody solution and the secondary antibody solution both contain NaN3, H+, C1- and tromethamine; preferably, wherein the AKRIC3 monoclonal antibody solution and the secondary antibody solution are obtained by diluting with an antibody dilution buffer, wherein the antibody dilution buffer comprises the following components: 0.02~0.08 mol/L of Tris-HCl buffer, containing 0.05~0.15% mass concentration of polyethylene glycol or Tween, and 0.010~0.020 mol/L of sodium azide; more preferably, the antibody dilution buffer comprises the following components: 0.05 mol/L of Tris-HCl buffer, containing 0.1 % mass concentration of polyethylene glycol or Tween, and 0.015 mol/L of sodium azide”. The limitations “0.02~0.08 mol/L…0.05~0.15%...0.010~0.020 mol/L” are unclear because these could be interpreted to be ranges or one approximate value. Furthermore, the limitation “~” is indefinite given that the specification fails to clearly define how much this approximation symbol encompasses. Also, the phrases “preferably” and “more preferably” render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention.
Furthermore, claim 6 contains the trademark/trade name Tween in lines 7 and 11. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe polysorbate and, accordingly, the identification/description is indefinite.
Claim 8 recites “wherein in the primary antibody incubation of step b ), the antigen-retrieved formalin-fixed paraffin-embedded human tissue specimen is incubated with the AKRIC3 monoclonal antibody solution for 30~45 min; more preferably, the antigen-retrieved formalin-fixed paraffin-embedded human tissue specimen is incubated with the AKRIC3 monoclonal antibody solution for 45 min; and/or wherein in the secondary antibody incubation of step c), the primary antibody-incubated formalin-fixed paraffin-embedded human tissue specimen is incubated with the secondary antibody solution for 30~45 min; more preferably, the primary antibody-incubated formalin-fixed paraffin-embedded human tissue specimen is incubated with the secondary antibody solution for 30 min”. The limitations “30~45 min …030~45 min” are unclear because these could be interpreted to be ranges or one approximate value. Furthermore, the limitation “~” is indefinite given that the specification fails to clearly define how much this approximation symbol encompasses. Also, the phrases “more preferably” render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). A person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim.
Claim 11 recites “wherein after the secondary antibody incubation of step c), further comprising: d) staining and sealing staining the formalin-fixed paraffin-embedded human tissue specimen using hematoxylin, and performing the dehydration and sealing of specimen after staining”. The limitation “d) staining and sealing staining” may be interpreted in multiple ways. For example this limitations appears to be a type of subheading, which is not proper, but it may also be interpreted to be a typographical error since it repeats the same limitation “staining”. Claim 11 recites the limitation "the dehydration and sealing" in line 5. There is insufficient antecedent basis for this limitation in the claim. It is not clear what is meant by “the dehydration and sealing” because a previous dehydration and sealing step is not recited in claim 11 or 1.
Claim 12 recites “wherein before the antigen retrieval of step a), further comprising: al) dewaxing and rehydration dewaxing the formalin-fixed paraffin-embedded human tissue specimen using an organic solvent, and washing the dewaxed specimen sequentially using alcohols containing different water contents, and finally washing with water; preferably, the organic solvent is acetone, toluene or xylene; more preferably, the organic solvent is xylene; and/or, preferably, the alcohol is ethanol or methanol; more preferably, the alcohol is ethanol; and/or, preferably, the dewaxed specimen is first washed with anhydrous ethanol and then washed with ethanol having a volume fraction of 90~97%”. The limitation “al) dewaxing and rehydration dewaxing” may be interpreted in multiple ways. For example this limitations appears to be a type of subheading, which is not proper, but it may also be interpreted to be a typographical error since it repeats the same limitation “dewaxing”. Furthermore, the limitation “90~97%” is unclear. It is not clear if this is meant to be a range or one approximate value. The limitation “~” is indefinite given that the specification fails to clearly define how much this approximation symbol encompasses. Also, the phrases “preferably” and “more preferably” render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). A person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim
Claim 13 recites “wherein between the antigen retrieval of step a) and the primary antibody incubation of step b), further comprising: b1) blocking non-specific antigen co-incubating the antigen-retrieved formalin-fixed paraffin-embedded human tissue specimen with a blocking solution to block a non-specific antigen; preferably, the blocking solution is a serum of an animal from which the AKRIC3 monoclonal antibody is derived; more preferably, the blocking solution is mouse serum”. The limitation “b1) blocking non-specific antigen co-incubating” appears to be a type of subheading, which is not proper, but it may also be interpreted to be a typographical error since it recites “blocking non-specific antigen co-incubating”. A person having ordinary skill in the art would not recognize the metes and bounds of the claim. Also, the phrases “preferably” and “more preferably” render the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). A person having ordinary skill in the art would not be able to recognize the metes and bounds of the claim.
Furthermore, claim 13 is indefinite because the limitation “preferably, the blocking solution is a serum of an animal from which the AKRIC3 monoclonal antibody is derived; more preferably, the blocking solution is mouse serum” is unclear. How can a blocking solution comprising the serum of the same animal as the primary antibody solution allow blocking? Indeed, it is expected that the secondary antibody, which targets the primary, would be targeting the blocking serum since it most likely contains antibodies of the same species as the primary antibody. A person having ordinary skill in the art would question the metes and bounds of the claim.
Claims 10 and 14 are included in this rejection because they depend from rejected claim 1 but fail to clarify the scope of patent protection sought.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 5 and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Ashley et al. Urology Volume 76, Issue 1, July 2010, Pages 67-72 https://doi.org/10.1016/j.urology.2009.09.046 ("Ashley") in view of R&D Systems "Human Aldo-keto Reductase 1C3/AKR1C3 Antibody Monoclonal Mouse IgG1 Clone # 871701 Catalog Number: MAB7678" Rev. 2/7/2018-Cite No. A of IDS 2/7/2024 ("R&D") as evidenced by Vector Laboratories “Horse Anti-Mouse IgG Antibody (H+L), Biotinylated” (retrieved online https://vectorlabs.com/products/biotinylated-horse-anti-mouse-igg/?srsltid=AfmBOoqN63G6O0ct6zEZrprN8RHR-wMc5rLlcs9kMotM75wc2cViYwEp on 4/7/2026).
Regarding claims 1 and 5, although the claims are indefinite (see 112(b) rejection above), in the interest of compact prosecution, claim 1 is interpreted as reciting “AKR1C3 expression levels” (line 1), “a) an antigen retrieval step comprising performing antigen retrieval…90 to 115°C for 17 to 30 min” (lines 4-6), “b) a primary antibody incubation step comprising mixing…0.5 to 5.0 µg/ml…25 to 700 min” (lines 8-11), and “ and c) a secondary antibody incubation step comprising mixing…0.5 to 5.0 µg/ml…25 to 700 min” (lines 12-15). Claim 5 is interpreted as reciting “1.0 to 3.0 µg/ml”. Furthermore, claim 5 is interpreted as not requiring the limitations following “more preferably”.
Regarding claims 1 and 5, Ashley teaches “(AKR1C3) expression in surgically-removed cryptorchid testes” (Abstract). Ashley further suggests an AKR1C3 detection method, wherein AKR1C3 expression levels in isolated formalin-fixed paraffin-embedded human tissue specimen is detected by using immunohistochemical staining method (“Human tissues…formalin-fixed, paraffin-embedded cryptorchid testes and 1 adult testis… were obtained” page 68 col. 1 para. 3, “Immunohistochemical (IHC) Staining” page 68 col. 1 para. 4), comprising the following steps: a) an antigen retrieval step comprising performing antigen retrieval by heating the formalin-fixed paraffin-embedded human tissue specimen at 90 to 115°C for 17 to 30 min in the presence of an antigen retrieval solution (“Antigen retrieval was performed with citrate buffer at 90°C for 20 minutes” page 68 col. 1 para. 4), b) a primary antibody incubation step comprising mixing the antigen-retrieved formalin-fixed paraffin-embedded human tissue specimen with AKR1C3 monoclonal antibody solution for incubation for 25 to 700 min (“Slides were incubated with monospecific mouse anti-AKR1C3 monoclonal antibody, NP6G6.A6,10 diluted 1:200 in TBS with 1% BSA...Following primary antibody incubation at 4°C overnight, the sections were rinsed with TBS” page 68 col. 1 para. 4). Note that although Ashley fails to use the language “mixing”, the teaching of incubating the sample overnight with the antibody solution comprising 1% BSA inherently provides a step of mixing the sample with the antibody solution because the antibody solution would diffuse and effectively mix throughout the sample. Also, although Ashley fails to use the language “for 25 to 700 min” the teaching of “overnight” inherently provides the claimed incubation time range. The broadest reasonable interpretation of “overnight” incubation encompasses a time as small as 8 hours (e.g. typical time for sleeping overnight) which corresponds to 480 min. Ashley further suggests c) a secondary antibody incubation step comprising mixing the primary antibody-incubated formalin-fixed paraffin-embedded human tissue specimen with a 0.5 to 5.0 µg/ml concentration of secondary antibody solution and incubating for 25 to 700 min (“Biotinylated horse anti-mouse secondary antibody, diluted to 1:400 (Vector Laboratories, Inc., Burlingame, CA) with TBS and 1% BSA, was applied and incubated for 2 hours at room temperature” page 68 col. 1 para. 4). Similar to above, note that although Ashley fails to use the language “mixing”, the teaching of incubating the sample with the antibody solution comprising 1%BSA inherently provides a step of mixing the sample with the antibody solution because the antibody solution would diffuse and effectively mix throughout the sample. Note also that the secondary antibody taught by Ashley, the biotinylated horse anti-mouse from Vector Laboratories, has a concentration of “1.5 mg active conjugate/ml” (page 4 of Vector Laboratories). Therefore, the 1:400 dilution of the secondary antibody taught by Ashley corresponds to 3.75 μg/ml concentration. Ashley further teaches that “[u]sing the cryptorchid testis as a developmental model, one can study when the enzyme is expressed, where it is localized, and propose theories for why its presence is required. The goal of our study was to characterize AKR1C3 expression in surgically-removed cryptorchid testes” (page 67 col. 2 para. 2 and page 68 col. 1 para. 1).
Ashley fails to teach a primary AKR1C3 monoclonal antibody solution concentration of 1.0 to 3.0 μg/ml and/or a secondary antibody solution concentration of 1.0 to 3.0 μg/ml.
R&D teaches “Human Aldo-keto Reductase 1C3/AKR1C3 Antibody” (Title). R&D further teaches a 0.5 to 5.0 μg/ml concentration of AKR1C3 monoclonal antibody solution (“1-25 µg/mL” APPLICATIONS Immunohistochemistry page 1). R&D “recommends” a 0.5 to 5.0 μg/ml concentration of AKR1C3 monoclonal antibody solution for “immunohistochemistry” (“Recommended Concentration” APPLICATIONS Immunohistochemistry page 1). R&D further teaches that a “1.7 µg/mL” concentration enables the localization of “ Specific staining…localized to cytoplasm in epithelial cells” (DATA Immunohistochemistry page 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Ashley to rely on the 1.7 µg/mL concentration of primary monoclonal antibody taught by R&D because R&D teaches this is a recommended concentration for immunohistochemistry applications and enables the localization of AKR1C3 inside the cytoplasm in epithelial cells and Ashley is interested in immunohistochemistry of AKR1C3 and its localization. A person having ordinary skill in the art would have had a reasonable expectation of success because both Ashley and R&D teach monoclonal AKR1C3 antibodies for immunohistochemistry.
Regarding claim 2, although the claim is indefinite (see 112(b) rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “2.0 to 9.0…6.0 to 9.0…92 to 102°C for 18 to 25 min”. Furthermore, the claim is interpreted as not requiring the limitations following “preferably”. Ashley in view of R&D teach the method of claim 1 as discussed above.
Ashley in view of R&D further suggest wherein in the antigen retrieval of step a), the antigen retrieval solution includes sodium citrate antigen retrieval solution (page 68 col. 1 para. 4 of Ashley).
Regarding claim 10, Ashley in view of R&D teach the method of claim 1 as discussed above.
Ashley in view of R&D further suggest wherein in the primary antibody incubation of step b), the AK.RI C3 monoclonal antibody is a mouse monoclonal antibody; and/or, in the secondary antibody incubation of step c), the secondary antibody is a goat anti-mouse antibody, a rabbit anti-mouse antibody, a horse anti-mouse antibody or a donkey anti-mouse antibody (page 68 col. 1 para. 4 of Ashley).
Regarding claim 11, although the claim is indefinite (see 112(b) rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “d) a staining and sealing step comprising staining…a dehydration and sealing”. Ashley in view of R&D teach the method of claim 1 as discussed above.
Ashley in view of R&D further suggest d) a staining and sealing step comprising staining the formalin-fixed paraffin-embedded human tissue specimen using hematoxylin, and performing the dehydration and sealing of specimen after staining (“Slides were then counterstained with hematoxylin, dehydrated in graded alcohol, cleared in xylene, and mounted with coverslips” page 68 col. 1 para. 4 of Ashley).
Regarding claim 12, although the claim is indefinite (see 112(b) rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “a1) a dewaxing and rehydration step comprising dewaxing…”. Furthermore, the claim is interpreted as not requiring the limitations following “preferably”. Ashley in view of R&D teach the method of claim 1 as discussed above.
Ashley in view of R&D further suggest a1) a dewaxing and rehydration step comprising dewaxing the formalin-fixed paraffin-embedded human tissue specimen using an organic solvent, and washing the dewaxed specimen sequentially using alcohols containing different water contents, and finally washing with water; preferably, the organic solvent is acetone, toluene or xylene; more preferably, the organic solvent is xylene; and/or, preferably, the alcohol is ethanol or methanol; more preferably, the alcohol is ethanol (“For immunohistochemical (IHC) staining, slides were dewaxed in xylene and rehydrated in a series of graded ethanol to distilled water” page 68 col. 1 para. 4 of Ashley).
Regarding claim 13, although the claim is indefinite (see 112(b) rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “b1) a blocking nonspecific antigen step comprising co-incubating…”. Furthermore, the claim is interpreted as not requiring the limitations following “preferably” or “more preferably” . Ashley in view of R&D teach the method of claim 1 as discussed above.
Ashley in view of R&D further suggest b1) a blocking non-specific antigen step comprising co-incubating the antigen-retrieved formalin-fixed paraffin-embedded human tissue specimen with a blocking solution to block a non-specific antigen (“Nonspecific binding was blocked by incubation in TBS, supplemented with 10% goat serum and 1% bovine serum albumin (BSA) for 2 hours at room temperature” page 68 col. 1 para. 4 of Ashley).
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Ashley in view of R&D as evidenced by Vector Laboratories as applied to claim 1 above, and further in view of Yurchenko et al. (RU 2700410C1)-2019-09-17 ("Yurchenko") as evidenced by PanReac AppliChem (retrieved online https://www.itwreagents.com/germany/en/product/tris-for-molecular-biology/A2264 on 4/8/2026) and Alpha Chemistry “10X Tris-buffered Saline Recipe Calculator” (retrieved online https://www.alfa-chemistry.com/resources/10x-tris-buffered-saline-recipe-calculator.html#:~:text=Composition%20of%2010X%20TBS%20Solution,through%20a%200.22%20%CE%BCm%20filter. On 4/8/2026).
Regarding claim 6, although the claim is indefinite (indefinite (see 112(b) rejection above), in the interest of compact prosecution, the claim is interpreted as not requiring the limitations following “preferably” or “more preferably” . Ashley in view of R&D teach the method of claim 1 as discussed above.
Ashley in view of R&D further suggest wherein the AKRIC3 monoclonal antibody solution and the secondary antibody solution both contain, H+, C1- and tromethamine (“Tris-buffered saline (TBS) diluted…in TBS” page 68 col. 1 para. 4 of Ashley). Note that Tris is tromethamine as evidenced by PanReacAppliChem (“Tris…also known as tromethamine” page 1 para. 1). Also note that TBS contains H+ and C1- as evidenced by Alpha Chemistry (“A standard 10X TBS buffer typically consists of the following components:…Tris Base…NaCl…HCl…H2O” page 2 paras. 1-5). Although Alpha Chemistry fails to use the language “H+ and C1-”, the teachings of NaCl, HCl and H2O inherently provides the “H+ and “Cl-” claimed.
Ashley in view of R&D fail to teach NaN3. Note that NaN3 is sodium azide.
Yurchenko teaches “immunohistochemistry” (para. 1) “to improve the quality of visualization of cells and tissues of large biological objects” (para. 13). Yurchenko further teaches wherein the primary antibody solution and the secondary antibody solution both contain sodium azide (“The stated problem is solved in that in the known method of immunostaining of biological material for confocal microscopy, including preparation of the material, fixation, removal of the fixative, blocking of non-specific binding of antibodies, incubation with primary antibodies in a blocking buffer, washing off the primary antibodies, incubation with secondary antibodies in a blocking buffer, washing off the secondary antibodies, dehydration, clarification and visualization of the object, according to the invention, a phosphate buffer containing 0.1-1.0% non-ionic detergent, 20.0% dimethyl sulfoxide, 1.0% bovine serum albumin, no more than 10.0% sheep serum and 0.03% sodium azide is used as a blocking buffer” para. 14). Yurchenko further suggests that the sodium azide enables “one to exclude non-specific staining throughout the entire depth of the sample and subsequently label only the structures of scientific interest and obtain a clear image of the desired structures” (para. 19)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Ashley in view of R&D to rely on the primary antibody solution and the secondary antibody solution both containing sodium azide taught by Yurchenko because Yurchenko suggests this helps exclude non-specific staining thus improving the quality of visualization of cells and tissues of large biological objects. A person having ordinary skill in the art would have had a reasonable expectation of success because both Ashley in view of R&D and Yurchenko teach an immunohistochemical staining method comprising a primary and secondary antibody solution containing a buffer.
Claims 8 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Ashley in view of R&D as evidenced by Vector Laboratories as applied to claim 1 above, and further in view of Yao et al. Am J Surg Pathol 2006;30:705–712 (“Yao”). Regarding claim 8, although the claim is indefinite (indefinite (see 112(b) rejection above), in the interest of compact prosecution, the claim is interpreted as reciting “30 to 45 min”. Furthermore, the claim is interpreted as not requiring the limitations following “more preferably”. Ashley in view of R&D teach the method of claim 1 as discussed above.
Ashley in view of R&D fail to teach wherein in the primary antibody incubation of step b), the antigen-retrieved formalin-fixed paraffin-embedded human tissue specimen is incubated with the AKRIC3 monoclonal antibody solution for 30 to 45 min; and/or wherein in the secondary antibody incubation of step c), the primary antibody-incubated formalin-fixed paraffin-embedded human tissue specimen is incubated with the secondary antibody solution for 30 to 45 min.
Yao teaches “small cell carcinoma of the prostate: an immunohistochemical study” (Title). Yao further teaches that “Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue sections using the antibodies listed in Table 1” (page 706 col. 1 para. 3 and col. 2 para. 1). Yao further teaches an antigen retrieval step by heating the formalin-fixed, paraffin-embedded tissue sections to 90 to 115°C for 17 to 30 min (“Antigen unmasking was performed by one of the following methods: …heat-retrieval with citrate buffer, pH 6.1 (DakoCytomation, Carpinteria, CA) with preheated (95 to 99°C) in a Black and Decker steamer (Shelton, CT, Model HS800) for 30 or 40 minutes” page 706 col. 2 para. 1). Yao further suggests the antigen-retrieved formalin-fixed paraffin-embedded tissue specimen is incubated with the primary antibody solution for 30 to 45 min (“All sections were incubated with the primary antibodies at room temperature for 45 to 60 minutes” page 706 col. 2 para. 1). Yao further suggests the primary antibody-incubated formalin-fixed paraffin-embedded tissue specimen is incubated with the secondary antibody solution for 30 to 45 min (“sections were then incubated for 30 minutes with the link antibody (rabbit or mouse) labeled polymer-HRP (Envision Plus System, DakoCytomation, Carpinteria, CA) or by 30-minute incubations with goat antirabbit IgG-Biotin or horse antimouse IgG Biotin and Streptavidin-HRP” page707 col. 1 para. 1). Yao suggests that “Immunohistochemical markers can help separate SCPC from HGPC and may be useful in histologically borderline cases. Potential therapeutic targets are identified immunohistochemically in SCPC (Bombesin/GRP, c-kit, bcl-2, and EGFR)” (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Ashley in view of R&D to rely on the primary and secondary antibody incubation of 30 to 45 min taught by Yao because Yao suggests this enables the identification of immunohistochemical markers for potential therapeutic targets and Ashley in view of R&D are interested in immunohistochemical detection methods. A person having ordinary skill in the art would have had a reasonable expectation of success because both Ashley in view of R&D and Yao teach an antigen retrieval step of heating the formalin-fixed, paraffin-embedded tissue sections to 90 to 115°C for 17 to 30 min, a subsequent primary antibody incubation step and then a secondary antibody incubation step.
Regarding claim 14, Ashley in view of R&D teach the method of claim 1 as discussed above.
Ashley in view of R&D fail to teach wherein the formalin-fixed paraffin-embedded human tissue specimen is breast cancer tissue specimen, colorectal cancer tissue specimen, esophageal cancer tissue specimen, gastric cancer tissue specimen, hepatocellular carcinoma tissue specimen, non-small cell lung cancer tissue specimen, prostate cancer tissue specimen, renal cell carcinoma specimen, peripheral T-cell lymphoma specimen or nodular NK/T-cell lymphoma specimen.
Yao teaches wherein the formalin-fixed paraffin-embedded human tissue specimen is prostate cancer tissue specimen (“The purpose of the current investigation is to begin to develop a comprehensive immunophenotypic profile of a relatively large number of multi-institutionally derived cases of SCPC [small cell carcinoma of the prostate (SCPC)]” page 705 col. 2 para. 2). Yao further teaches that “[t]he immunophenotypic profile that is developed is compared to that of small cell lung carcinoma and Gleason pattern 5b prostate adenocarcinoma” (page 705 col. 2 para. 2). Yao further suggests that using the prostate cancer tissue specimen enables the study of the histogenesis of SCPC and identifying appropriate treatment targets, which is a current need in the field (“Extrapulmonary small cell carcinoma is rare; however, the prostate is one of the more common sites for extrapulmonary small cell carcinoma. Subsequent studies have characterized small cell prostate carcinoma as presenting at an advanced stage, lacking a response to antiandrogen therapy, and with rapid progression. The overall behavior and response to therapy of SCPC is similar to that of small cell lung carcinoma. …This study is of value for several reasons: (1) treatment targets can be identified which are similar to, or different from, prostatic adenocarcinoma and small cell lung carcinoma… (2) Knowledge of the immunophenotypic profile of morphologically typical SCPC and Gleason pattern 5b prostate adenocarcinoma may be of help in identifying and classifying morphologically borderline cases for further pathologic studies and/or appropriate assignment in randomized clinically trials. (3) Immunophenotypic profiling could aid in the rare instances of SCPC presenting as a tumor of unknown origin. (4) Immunophenotypic variation between Gleason pattern 5b prostate adenocarcinoma, SCPC, and small cell lung carcinoma can shed light on the histogenesis of small cell carcinoma in general and SCPC in particular” page 705 col. 2 para. 2 and page 706 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Ashley in view of R&D to rely on the prostate cancer tissue specimen taught by Yao because Yao suggests this enables the study of the histogenesis of SCPC and identifying appropriate treatment targets for SCPC, a current need in the field. A person having ordinary skill in the art would have had a reasonable expectation of success because both Ashley in view of R&D and Yao teach an antigen retrieval step of heating the formalin-fixed, paraffin-embedded tissue sections to 90 to 115°C for 17 to 30 min, a subsequent primary antibody incubation step and then a secondary antibody incubation step.
Conclusion
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
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