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.
Withdrawn Rejection
The rejection to claim 4 under 112b is withdrawn in response to the amendments. However, upon further consideration, new grounds of rejection are set forth below.
Priority
The present application was filed on 5/18/2022 and is a CON of PCT/JP2020/043393, filed 11/20/2020. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. JP2019-209679, filed on 11/20/2019 in Japan.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of the Claims
Claims 1-15 are pending; claims 1-12 are amended; claims 14-15 are newly recited; claim 13 is withdrawn. Claims 1-12 and 14-15 are examined below .
New Rejection
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 12 and 14-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 12 and its dependent claims require “providing an antifungal drug to the animal when the threshold is exceeded”.
However, the specification only discloses that “[a]ntifungal drugs are usually given to patients who are diagnosed as having pathogenic fungi present in the body causing deep mycosis such as Aspergillus and Candida by the deep mycosis test” (para 4); and “if the fungal-derived β-glucan and the plant-derived β-glucan cannot be distinguished…plant-derived β-glucan may become false positives, resulting in erroneous diagnosis of deep mycosis and unnecessary administration of antifungal drugs” (para. 8). The disclosures regarding the “antifungal drug” seem to be providing background on the state of the art and do not appear to be referring to active treatment methods of the invention, i.e. a step of “providing an antifungal drug to the animal when the threshold is exceeded”. The language “[a]ntifungal drugs are usually given to patients who are diagnosed” (emphasis added) suggests that this a conventional method used in the art, which is not the same as contemplating the step as part of the invention. Similarly, the language used in paragraph 8, “plant-derived β-glucan may become false positives, resulting in erroneous diagnosis of deep mycosis and unnecessary administration of antifungal drugs”, does not seem to contemplate the step of administering antifungal drugs as part of the invention; rather, paragraph 8 seems to merely illustrate the consequences of false positive detections. Therefore, Applicant does not have support for claims 12 and 14-15, i.e. the claims recite new matter.
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 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 12 recite “…(ii) a molecule that specifically binds to a β-(1➔3) bond, and (iii) molecule that specifically binds to a β-(1➔6) bond… performing a solid-liquid separation step to remove from the test sample (a) labeled molecule (ii) or (iii) that is bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan…”.
However, given that the specification suggests that β-glucan can either have β-(1➔3) bonds and β-(1➔6) bonds, or β-(1➔3) bonds and β-(1➔4) bonds (paragraph 3), a molecule that specifically binds to a β-(1➔6) bond would inherently only bind to β-1,3-1,6-glucan (“The β-glucan contained in fungi and bacteria mainly contains β-(1➔3) bonds and β-(1➔6) bonds, and the β -glucan contained in plants mainly β-(1➔3) bonds and β-(1➔4) bonds” para. 3). Therefore, it is not clear how molecule (iii) which specifically binds to a β-(1➔6) bond, is bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan.
Claims 2-12 and 14-15 are included in this rejection because they depend on rejected claims 1 and 12 but do not clarify the scope of patent protection sought.
Claim 4 recites “wherein said molecule that specifically binds to a β-(1➔3) bond is removed in the solid-liquid separation step”. However, it is not clear how “said molecule that specifically binds to a β-(1➔3) bond is removed in the solid-liquid separation step” because said molecule that specifically binds to a β-(1➔3) bond forms a complex with β-glucan and a molecule that specifically binds to a β-(1➔6) bond. Notably, the specification paragraph 41 discloses that “the free labeling material is removed by making use of a solid-liquid separation treatment”, not the elements of the complex. Therefore, it is unclear how “said molecule that specifically binds to a β-(1➔3) bond is removed in the solid-liquid separation step”.
For these reasons the claims are indefinite.
Maintained Rejection
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 12 and 14-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Prong One asks does the claim recite an abstract idea, law of nature, or natural phenomenon? In Prong One examiners evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim. While the terms "set forth" and "described" are thus both equated with "recite", their different language is intended to indicate that there are two ways in which an exception can be recited in a claim. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims "set forth" an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words "intermediated" or "settlement." See MPEP 2106.04 (II)(A)(1).
The claim recites “diagnosing a likelihood of a fungal infection…measuring an amount of β-1,3-1,6-glucan in said test sample based on a result of said detection against a threshold value for the likelihood of a fungal infection in the animal from which the biological sample derives…”
The natural relationship to which the claims are directed (i.e., the relationship between β-1,3-1,6-glucan and fungal infection) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring amount of β-1,3-1,6-glucan in a test sample and the presence of fungal infection.
The correlation between the amount of β-1,3-1,6-glucan and disease is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that the amount of β-1,3-1,6-glucan is elevated to different extents in fungal infection vs. in other diseases.
Step 2A, Prong 2
The additional elements of the claim, including the steps of “mixing (i) a biological sample collected from a test animal, (ii) a molecule that specifically binds to a β-(1➔3) bond, and (iii) a molecule that specifically binds to a β-(1➔6) bond to form a test sample, wherein one of molecule (ii) or (iii) is labeled and the other is immobilized on a solid phase support so as to form a complex, wherein the solid phase support is collected in the test sample; performing a solid-liquid separation step to remove from the test sample (a) labeled molecule (ii) or (iii) that is bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan, and (b) any unbounded labeled molecule (ii) or (iii); detecting from said complex immobilized molecule (ii) or (iii) and β-1,3-1,6-glucan bound thereto that remains in the test sample”, fails to integrate the judicial exceptions into a practical application because this is insignificant presolution activity. The purpose of the steps above are merely to gather data in order to make the correlation similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps of measuring β-1,3-1,6-glucan are recited at a high level of generality and are not tied, for example, to any particular machine or apparatus.
Claim 12 further recites “providing an antifungal drug to the animal when the threshold is exceeded”. This step is insufficient to integrate the judicial exception as (1) it does not clearly require an active treatment step to be administered to the animal and (2) it is not limited to a particular treatment.
(1) The language “providing” does not clearly limit the claim to a treatment step and may be interpreted as a step that is not actively treating the animal. Given the broad language used, this step does not integrate the judicial exception.
(2) The recited step of “providing an antifungal drug to the animal” is recited at a high level of generality and is not limited to a particular antifungal drug. Such highly generalized limitations – which do not require any specific antifungal drugs for fungal infection – do not amount to sufficient practical application to provide patentability. Although a claim limitation can integrate a judicial exception by applying or using the judicial exception(s) to effect a particular treatment or prophylaxis for a disease or medical condition, in this case no specific or particular treatment is set forth.
The level of generality in the instant claims stands in contrast to the treatment claims found patent-eligible in Vanda Pharm. Inc. v. West-Ward Pharm. Int' l Ltd., 887 F.3d 1117 (Fed. Cir. 2018) and Natural Alternatives Int' l v. Creative Compounds LLC, 2017 WL 1216226 (Fed. Cir. Mar. 15, 2019). The claims at issue in Vanda recited administering a specific drug (iloperidone) at specific dosage ranges based on a patient' s genotype. Vanda, 887 F.3d at 1135. Accordingly, the court found that although the inventors recognized the relationships between iloperidone, a patient' s genotype, and QTc prolongation, what they claimed is “an application of that relationship,” i.e., “‘a new way of using an existing drug' that is safer for patients because it reduces the risk of QTc prolongation.” Id. (quoting Mayo, 566 U.S. at 87). The Federal Circuit characterized the Vanda claims as being directed to “a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.” Id. at 1136. Similarly, the Federal Circuit found that the claims in Natural Alternatives “contain specific elements that clearly establish they are doing more than simply reciting a natural law,” such as specifying a patient population, particular results to be obtained, specific compounds to be administered to achieve the claimed results, and dosages via an “effective” limitation. Natural Alternatives, 4-5.
In contrast to the claims in Vanda and Natural Alternatives, the present claims do not specify a particular result to be obtained, a compound to be administered to achieve a claimed result, or any specific dosage of a specific compound.
Here, the claimed step of “providing an antifungal drug to the animal when the threshold is exceeded” instead merely an instruction to “apply” the exception in a generic way. Therefore, it does not integrate the judicial exception into a practical application.
Claim 14 limits the molecule that specifically binds to a β-(1➔3) bond to be labeled with a labeling material and claim 15 limits the molecule that specifically binds β-(1➔6) bond to be immobilized on a solid phase support. Therefore, claims 14-15 also fail to integrate the judicial exception(s) into a practical application because this are insignificant presolution activity, i.e. limitations drawn to data gathering. Claims 14-15 fail to use, rely on or apply the judicial exception such to amount to a practical application thereof.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claim, including the steps to measure β-1,3-1,6-glucan in biological samples, do not add significantly more to the judicial exception(s).
In this case, it was well-understood, routine and conventional to measure β-1,3-1,6-glucan in biological samples. See for example:
Akito (EP 2410337 B1) teaches that “βG has a structure of repeated glucose unit linked by (1 ➔3) bond as a main chain, and in some cases it has branched structure with (1 ➔6) bond” (paragraph 3). Akito further teaches that “[a] representative example of causative microorganism of the deep-seated mycotic disease includes species of Candida and Aspergillus, and since the βG is present commonly in the cell walls of both species, it is useful to determine blood level of the βG. In the clinical diagnosis, determination of plasma or serum β-glucan level is used for earlier diagnosis of fungal infection, determination of therapeutic effect and prognosis” (paragraph 2).
Warmington and Ballantyne (CN 1505759 A) (“Warmington”) teach that “[a]t present, several commercial immunoassay can be used for detection of Candida albicans antigen in serum or other body fluids” (page 3 paragraph 2). Note that candida albicans is a type of β-glucan as per the specification paragraph 67 and 70 (“types of β-glucans with different origins” paragraph 70).
Theel and Doern J Clin Microbiol. 2013 Nov;51(11):3478–3483. doi: 10.1128/JCM.01737-13 (“Theel”) teach that “β-D-Glucan testing is important for diagnosis of invasive fungal infections” (Title). Theel further teaches that “[d]etection of fungal antigens in body fluids, including …β-d-glucan, is viewed as being clinically useful” (Abstract).
Furthermore, the specification paragraph 45 discloses that “The solid-liquid separation treatment is not particularly limited as long as it is a method capable of recovering the solid phase support in the solution in a state of being separated from the liquid component, and can be appropriately selected and used from among the known treatments used for the solid-liquid separation treatment”.
Also, there is evidence that a molecule that specifically binds to β-(1➔3) bond labeled with a labeling material is well-understood, routine and conventional.
Akito teaches a molecule that specifically binds to β-(1➔3) bond labeled with a labeling material (“βG-binding protein 2 which is labeled with a labeling substance” claim 5, paras. 31-32).
Also, Rachini et al. Infect Immun . 2007 Jul 2;75(11):5085–5094. doi: 10.1128/IAI.00278-07 (“Rachini”) teaches “using gold-labeled antibodies against (1,3)-linked β-glucan” (page 5086 col. 1 para. 2).
There is also evidence that a molecule that specifically binds to β-(1➔6) bond immobilized on a solid phase support is well-understood, routine and conventional.
Yamanaka et al. (US 11,479,803 B2) ("Yamanaka) teaches “the β-1 ,6-glucanase mutant E321X and/or E225X/E321X are immobilized to an insoluble carrier” (col. 3 lines 27-28).
Sung et al. SCIENTIFIC REPORTS | (2018) 8:13652 | DOI:10.1038/s41598-018-31961-x (“Sung”) teaches that they “have generated recombinant antibodies (rAbs) against SCH by antibody phage display. Next to SCH, these antibodies were identified to bind also to other similar β-(1,6)-branched β-(1,3)-D-glucans” (page 1 para. 2).
Jung et al. Analyst, 2008, 133, 697–701 (“Jung”) teaches that “[a]ntibody immobilization on a solid support is an essential process for the development of most immune-based assay systems” (Abstract).
Furthermore, it was also well-understood, routine and conventional to provide an antifungal drug to the animal when the threshold is exceeded.
For example, Pyrpasopoulou et al. J Emerg Crit Care Med 2019;3:37 | http://dx.doi.org/10.21037/jeccm. (“Pyrpasopoulou”) teaches that “[c]ritically ill patients suffer from invasive fungal infections, mainly due to Candida spp., but also to Aspergillus spp., Cryptococcus spp. and other more rare yeasts or filamentous fungi. These infections are prevented or treated with various antifungal agents” (Abstract).
Also, Owens et al. US Pharm. 2010;35(8):44-56. (“Owens”) teaches that “[f]or over two decades, the azole antifungals have been used in clinical practice to treat various fungal infections (TABLE 1)” (page 2 para. 3).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Maintained Rejection
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 1-10, 12 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Akito (EP 2410337 B1) in view of Yamanaka et al. (US 11,479,803 B2) ("Yamanaka).
Regarding claims 1 and 12, although the claims are indefinite (see 112b rejection above), in the interest of compact prosecution, claims 1 and 12 are interpreted as reciting “…to remove from the test sample (a) labeled molecule (ii) that is bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan…”. Akito suggests a method for measuring β-1,3-1,6-glucan (“[t]he present invention relates to a novel method for measuring β-glucan {hereinafter, abbreviated as "βG")” paragraph 1, “βG has a structure of repeated glucose unit linked by (1 ➔3) bond as a main chain, and in some cases it has branched structure with (1 ➔6) bond or (1 ➔4) bond” paragraph 3), comprising: mixing (i) a β-glucan, (ii) a molecule that specifically binds β-glucan, and (iii) a molecule that specifically binds β-glucan to form a test sample (“contacting a sample with a protein 1… having a β-glucan binding activity {hereinafter, abbreviated as "βG-binding protein 1 "), and also a protein 2… having a β-glucan binding activity {hereinafter, abbreviated as "βG-binding protein 2 to form a complex of the βG-binding protein 1, βG in the sample and the βG-binding protein 2" claim 1, “The sample involved in the present invention includes a clinical sample such as, for example, blood, serum, plasma, urine, lymph, cerebrospinal fluid, pleural effusion, and ascites fluid; medical drug; medical device; food; and the like, however, the sample is not limited thereto” para. 133). Akito suggests that the molecules binding β-glucan target the β-1,3-glucan bond (“[t]he "βG-binding protein 1" and the "βG-binding protein 2" are the ones derived from factor G-subunit α of hemocyte of horseshoe crab” paragraph 31, “[t]he amino acid sequence of the factor G-subunit a of horseshoe crab…comprises… a β-1,3-glucanase-like domain” paragraph 32, “Measurement of βG by various βG-binding proteins” paragraph 238, “Example 1, β-1,3-glucan recognition protein derived from silkworm” paragraph 240, “In the hemolymph of Indian meal moth (Plodia interpunctella), there exists βG recognition protein (β-1, 3-glucan recognition protein)” paragraph 247, “In addition, the followings were used as a βG-binding protein.* Dectin-1 derived from mouse (produced by R&D Systems, Inc.); * Mouse anti-(1, 3) βG antibody (produced by Biosupplies Australia Pty Ltd.)” paragraph 251). Akito further suggests wherein one of molecule (ii) or (iii) is labeled and the other is immobilized on a solid phase support so as to form a complex (“(1) contacting a sample with the βG-binding protein 1 which is immobilized to an insoluble carrier, to form a complex-1 of βG in the sample and the βG-binding protein 1 immobilized to the insoluble carrier; (2) contacting the aforementioned complex-1 with the βG-binding protein 2 which is labeled with a labeling substance, to form a complex-2 of the complex-1 and the labeled βG-binding protein 2; (3) measuring quantity of the labeling substance in the aforementioned complex-2” claim 5). Akito further suggests wherein the solid phase support is collected in the test sample (“As to the insoluble carrier which is used for immobilizing βG-binding protein involved in the present invention in the method for measuring βG of the present invention, any carrier can be used as long as it is used, for example, in the conventional immunological measurement methods” para. 85, “The method for supporting the βG-binding protein involved in the present invention by the above described carrier is not particularly limited, as long as the βG-binding protein is brought into contact with the carrier. The supporting method includes the one well known per se and usually used in this field (for example, so-called physical adsorption method) as a representative example” para. 116). Note that although Akito fails to use the language “wherein the solid phase support is collected in the test sample”, the teachings that the carrier is used “in the conventional immunological measurement methods” and that the carrier supports by physical adsorption the βG-binding protein by bringing into contact the βG-binding protein and the carrier, inherently provides “wherein the solid phase support is collected in the test sample” because the solid phase support would only support and physically adsorb the βG-binding protein if the solid phase support is collected in the sample. Akito further suggests performing a solid-liquid separation step to remove from the test sample (a) labeled molecule (ii) that is bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan, and (b) any unbound labeled molecule (ii) or (iii) (para. 3, “a microplate and a bead are preferable particularly from the viewpoints, such as easiness of washing” para. 85, “Example 2: Measurement of βG…50 μL of sample…was added to each well of the βG-binding protein-immobilized micro plate for ELISA prepared in the above 1), and reacted at 37°C for 1 hour. Subsequently, each well was washed 3 times with PBS-T … 50 μL of the peroxidase-labeled βG-binding protein (2 μg/ml) prepared in the above 2) was dispensed in each well, and reacted at 37°C for 1 hour. After washing each well 3 times with PBS-T and once with distilled water, 50 μL of TMB…was added to each well” paras. 238 and 257). Note that although Akito fails to use the language “performing a solid-liquid separation step to remove from the test sample (b) any unbound labeled molecule (ii) or (iii)” the teaching of using a solid phase support with said complex, together with multiple washing steps inherently provides a solid-liquid separation step to remove from the test sample (b) any unbound labeled molecule (ii) or (iii) because the washing steps effectively remove any unbound labeled molecule (ii) or (iii). Note also that although Akito fails to use the language “a solid-liquid separation step to remove from the test sample (a) labeled molecule (ii) that is bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan” the teaching of measuring βG using the solid phase support and washing steps described above, together with the teaching that the βG “has branched structure with (1 ➔6) bond” (para. 3) reads on a solid-liquid separation step to remove from the test sample (a) labeled molecule (ii) that is bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan because the washing steps would remove any molecule (including (a) labeled molecule (ii) that is bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan) that is not immobilized in a complex to the solid phase support. Importantly, the teachings of Akito encompass the capture and detection of β-1,3-1,6-glucan based on the teaching of measuring βG and that βG “in some cases…has branched structure with (1 ➔6) bond” (para. 3). Akito’s teachings also encompass removing labeled molecule (ii) bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan because labeled molecule (ii) bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan is not necessarily part of said complex, particularly when β-1,3-1,6-glucan is captured and detected as part of the complex. For example, labeled molecule (ii) bound to β-glucan wherein the β-glucan is not β-1,3-1,6-glucan could be labeled molecule (ii) bound to β-1,3-1,4-glucan (“in some cases it [βG] has branched structure with… (1 ➔4) bond” para. 3) that is not part of the complex immobilized on the solid phase support, and the washing step is performed to isolate and detect the complex (“It should be noted that after respective operations, an operation to remove unwanted substance (washing or the like) may be carried out, if necessary” para. 64). Akito further suggests detecting from said complex immobilized molecule (ii) or (iii) and β-1,3-1,6-glucan bound thereto that remains in the test sample(“measuring quantity of the aforementioned complex” claim 1, “Absorbance at 450 nm was measured” para. 257); and measuring an amount of β-1,3-1,6-glucan in said test sample based on a result of said detection (“determining βG concentration in the sample based on the quantity of the complex obtained” claim 1). Akito further suggests a method for diagnosing a likelihood of a fungal infection comprising: using a biological sample collected from a test animal as a test sample and measuring an amount of β-1,3-1,6-glucan in said test sample based on a result of said detection against a threshold value for the likelihood of a fungal infection in the animal from which the biological sample derives (“[i]n the clinical diagnosis, determination of plasma or serum β-glucan level is used for earlier diagnosis of fungal infection, determination of therapeutic effect and prognosis” paragraph 2). Note that although Akito fails to use the language “measuring an amount of β-1,3-1,6-glucan in said test sample based on a result of said detection against a threshold value for the likelihood of a fungal infection in the animal from which the biological sample derives” the teaching that “[i]n the clinical diagnosis, determination of plasma or serum β-glucan level is used for earlier diagnosis of fungal infection” together with the teaching that “βG has…branched structure with (1 ➔6) bond” inherently provides a step of “measuring an amount of β-1,3-1,6-glucan in said test sample based on a result of said detection against a threshold value for the likelihood of a fungal infection in the animal from which the biological sample derives” because measuring a β-glucan level (i.e. β-1,3-1,6-glucan) for use in the clinical diagnosis of fungal infection would necessarily entail a threshold value for determining the likelihood of a fungal infection on the patient being examined.
Akito fails to teach a molecule that specifically binds to a β-(1 ➔6) bond and providing an antifungal drug to the animal when the threshold is exceeded.
Yamanaka teaches that “β-Glucan is a main polysaccharide constituting a fungal cell wall and is roughly divided into β-1 ,3-glucan, a polysaccharide in which glucose molecules are linked by β-(1➔3 bonds), and β-1 ,6-glucan, a polysaccharide composed of β-(1➔6) bonds” (col. 1 lines 13-17). Yamanaka further teaches (ii) a molecule that specifically binds to a β-(1 ➔3) bond (“recognition system of β-1,3-glucan is applied in a medical field. Limulus factor G, a β-1 ,3-glucan recognition protein derived from horseshoe crabs, is used as an in-vitro diagnostic drug for detecting β-1 ,3-glucan in human blood (LAL method)” col. 1 lines 26-31), and (iii) a molecule that specifically binds to a β-(1 ➔6) bond (“[a]n object of the present invention is to provide a novel material having a specific binding activity to β-1,6-glucan… inventors prepared a β-1,6-glucanase mutant…which… had a specific binding activity to β-1,6-glucan” col. 2 lines 21-35). Yamanaka further teaches that measuring both β-(1➔3 bonds) and β-(1➔6) bonds is preferable for diagnosing fungal infections to prevent false positive detections (“since β-1,6-glucan is not contained in plant cell walls, it can be expected to be an indicator that is unlikely to produce a false positive… there are fungi in which polysaccharides constituting cell walls only contain β-1,6-glucan or hardly contain β-1 ,3-glucan (for example, Pustulan, Islandican, etc. as shown in Table 1 below), it is preferable to perform not only LAL test using β-1,3-glucan as an indicator but also detection of β-1 ,6-glucan at the time of diagnosing fungal infections” col. 2 lines 3-6 and 10-17). Yamanaka further suggests providing an antifungal drug to the animal when the threshold is exceeded (“The present invention enables rapid and highly sensitive measurement of β-1,6-glucan that was impossible in the related art, such that diagnosis accuracy of fungal infection can be significantly improved. In addition, it becomes easy to determine the timing of continuation or termination of the antifungal drug administration by monitoring a concentration of β-1,6-glucan in the blood, such that an antifungal drug often causing side effects can be appropriately used” col. 3 lines 32-39). Note that although Yamanaka fails to use the language “when the threshold is exceeded”, the teaching of monitoring a concentration of β-1,6-glucan in the blood and then administering the antifungal drug to the patient accordingly, suggests “when the threshold is exceeded” because the antifungal drug would only be administered based on the concentration of β-1,6-glucan in the blood, i.e. when the threshold is exceeded.
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 modify the teachings of Akito to substitute a molecule (iii) that targets β-glucan to be specific for the β-(1➔6) bond taught by Yamanaka because Yamanaka teaches that this prevents false positive diagnosis of fungal infections. It would have been further obvious to have modified the teachings of Akito to include providing an antifungal drug to the animal when the threshold is exceeded taught by Yamanaka because Yamanaka suggests that this enables appropriate antifungal drug treatment, i.e. avoids unnecessary side effects. A person having ordinary skill in the art would have had a reasonable expectation of success because both Akito and Yamanaka are drawn to methods involving measuring β-glucan for diagnosing fungal infections.
Regarding claim 2, Akito in view of Yamanaka suggests the method of Claim 1, wherein said molecule that specifically binds to a β-(1➔6) bond is an enzyme-inactivated mutant of β-1,6-glucanase (“a β-1,6-glucanase mutant in which an amino acid residue present in a catalytic enzyme region of β-1,6-glucanase, which is a β-1,6-glucan degrading enzyme, was substituted by another amino acid residue, and the present inventors found that the mutant in which a specific amino acid residue was substituted did not have a β-1,6-glucan cleavage activity and had a specific binding activity to β-1,6-glucan” col.2 lines 27-34 of Yamanaka).
Regarding claim 3, Akito in view of Yamanaka suggest the method of Claim 1, wherein said molecule that specifically binds to a β-(1➔3) bond is at least one selected from the group consisting of a horseshoe crab-derived factor G or a mutant thereof, a protein containing a carbohydrate recognition domain of dectin-1 or a mutant thereof, a β-glucan recognition protein or a mutant thereof, and an anti-β-1,3-glucan antibody (paragraphs 31-32, paragraph 238, paragraph 240, paragraph 247 and paragraph 251 of Akito).
Regarding claim 4, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, it is interpreted that the molecule that specifically binds to a β-(1➔3) bond is not part from said complex as per paragraph 41 of the specification. Akito in view of Yamanaka suggest the method of Claim 1, wherein said molecule that specifically binds to a β-(1➔3) bond is removed in the solid-liquid separation step (“preferably after the complex is formed, the aforementioned complex is separated from free βG-binding protein 1 and free βG-binding protein 2 by capillary electrophoresis” claim 2, paras. 64 and 257 of Akito).
Regarding claims 5-6 and 14-15, Akito in view of Yamanaka suggest the method of Claims 1 and 12, wherein said molecule that specifically binds to a β-(1➔3) bond is labeled with a labeling material, wherein said molecule that specifically binds to a β-(1➔6) bond is immobilized on a solid phase support (“(1) contacting a sample with the βG-binding protein 1 which is immobilized to an insoluble carrier, to form a complex-1 of βG in the sample and the βG-binding protein 1 immobilized to the insoluble carrier; (2) contacting the aforementioned complex-1 with the βG-binding protein 2 which is labeled with a labeling substance, to form a complex-2 of the complex-1 and the labeled βG-binding protein 2; (3) measuring quantity of the labeling substance in the aforementioned complex-2” claim 5 of Akito, col.2 lines 27-34 of Yamanaka).
Regarding claims 7-8, Akito in view of Yamanaka suggest the method of Claim 6.
Akito teaches wherein said solid phase support is a bead (“As to the insoluble carrier which is used for immobilizing βG-binding protein involved in the present invention…can be…a bead” paragraph 85) Akito further teaches that “[i]t should be noted that it is also possible to immobilize the βG-binding protein to an insoluble carrier by using very firm binding reaction like the avidin-biotin reaction commonly used in this field” paragraph 91).
Akito fails to teach a magnetic bead and fails to explicitly teach wherein said solid phase support is modified with a biotin-binding molecule and said molecule that specifically binds to a β-(1➔6) bond is a biotin-modified molecule.
Yamanaka teaches that “[i]n Example 6, β-glucan was successfully detected with high sensitivity from the pathogenic fungal culture supernatant, but there was a disadvantage in that it took several hours for detection. In order to shorten the time for detection, biotinylated E321Q was bonded to streptavidin-labeled magnetic beads (manufactured by Veritas Corp.)” (col. 12 lines 51-56).
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 modify the teachings of Akito to rely on the bead being magnetic and wherein said molecule is biotin-modified and the bead is modified with a biotin-binding molecule taught by Yamanaka because Yamanaka suggests this shortens the time for detection. A person having ordinary skill in the art would have had a reasonable expectation of success because Yamanaka teaches that magnetic beads are commercially available and both Akito and Yamanaka teach beads as insoluble carriers and immobilizing β-glucan binding molecules to the bead using avidin-biotin reactions commonly used in the field.
Regarding claim 9-10, Akito in view of Yamanaka suggest the method of Claim 5, wherein said labeling material is a luminescent material, and wherein said labeling material is a fluorescent material (“The labeling substance to be used…includes…fluorescent substances…luminescent substances” paragraph 92 of Akito).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Akito and Yamanaka as applied to claim 1 above, and further in view of Goix et al. (US 9040305 B2) (“Goix”).
Regarding claim 11, Akito in view of Yamanaka suggest the method of Claim 1 as discussed above.
Akito further teaches that “the measurement may be carried out according to the routine procedure using a measurement apparatus such as a photo counter” (paragraph 109).
Akito in view of Yamanaka fail to teach wherein said complex is detected by a scanning single-molecule counting method.
Goix teaches “methods of analysis for determining a specific protein in blood samples using fluorescence spectrometry” (Title). Goix further teaches that “[t]he invention encompasses analyzers and analyzer systems that include a single particle analyzer, methods of using the analyzers and analyzers systems to analyze samples, either for single particles, e.g., protein molecules, or for multiple particles (multiplexing)” (Abstract). Goix further suggests wherein said complex is detected by a scanning single-molecule counting method (“sampling a portion of the processed sample, where the sampling is performed by a sampling system that (i) is capable of automatically and sequentially sampling a plurality of processed samples from a multiwell container; and (ii) comprises a source of negative pressure to draw the portion of the processed sample into a sampling port” col. 1 lines 53-57, “The methods described herein allow particles (e.g., protein molecules) to be enumerated as they pass through the interrogation spaces one at a time, as described previously. The concentration of the sample can be determined from the number of particles counted and the volume of sample passing though the interrogation space in a set length of time” col. 16 lines 51-57). Goix further teaches that the scanning single-molecule counting method “provide increased sensitivity and the ability to multiplex samples” (col. 30 lines 18-19). Goix further suggests that the single-molecule counting method is used for measuring β-1,3-1,6-glucan in the diagnosis of sepsis (“[f]or example, for the diagnosis of sepsis, various combinations of the following diagnostic markers may be used: one or more pathogen markers for Candida albicans” col. 25 lines 21-22 and 28-29). Note that candida albicans is a type of β-glucan as per the specification paragraph 67 and 70 (“types of β-glucans with different origins” paragraph 70).
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 modify the teachings of Akito in view of Yamanaka to rely on the scanning single-molecule detection method taught by Goix because Goix teaches that this enables increased sensitivity and diagnosis of sepsis. A person having ordinary skill in the art would have had a reasonable expectation of success because Goix suggests that this method can be used to measure β-1,3-1,6-glucan.
Response to Arguments
Applicant's arguments filed 8/29/2025 have been fully considered but they are not persuasive.
Regarding the 101 rejections, Applicant argues that “Claim 12 has been amended to conform to Claim 1 to the extent required and to include a specific treatment step of "providing an antifungal drug to the animal when the threshold is exceeded." It is submitted that Claim 12 now recites proper and eligible subject matter for purposes of § 101” (page 7 para. 8 and page 8 para. 1). However, "providing an antifungal drug to the animal when the threshold is exceeded" fails to integrate the judicial exception or add significantly more than the judicial exception (see rejection above). The newly added limitation, “providing an antifungal drug to the animal when the threshold is exceeded" does not recite an active treatment step that is specific (see 101 rejection above for the complete analysis).
Regarding the 103 rejections, Applicant argues that “a method for measuring β-1,3-1,6-glucan…is undisclosed and unsuggested by the cited references” (page 8 para. 4). However, Akito suggests a method for measuring β-1,3-1,6-glucan given that Akito teaches measuring β-glucan and also teaches that β-glucan encompasses β-1,3-1,6-glucan (see citations above). Applicant further argues that “none of Aktia or Yamanaka teach or suggest the particular method steps of amended Claim 1 and its dependencies for measuring an amount of β-1,3-1,6-glucan in a test sample, as claimed” (page 8 para. 6). However, Akito in view of Yamanaka suggest the method of claims 1 and 12 and their dependencies (see rejection above). Applicant further argues that “[t]he tertiary reference to Goix is cited for the subject matter of Claim 11 and does not bring the combination of Akita and Yamanaka any closer to the amended claims for purposes of §103” (page 9 para. 2). However, there are no deficiencies in Akito in view of Yamanaka for addressing the amended claims.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677