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 .
DETAILED ACTION
1. The Amendment filed May 16, 2025 in response to the Office Actions of April 15, 2025 and November 20, 2024 is acknowledged and has been entered. Claims 3, 6-8, and 11 have been cancelled. Claims 1, 4, 9, 10, and 12 have been amended. New claims 22-24 have been added.
Election/Restrictions
2. In the response filed May 16, 2025, Applicant filed a Petition under 37 C.F.R. 1.144 and 1.181 along with arguments to withdraw the restriction requirement and rejoin all withdrawn claims.
In response to the Petition a decision under 37 C.F.R. 1.144 and 1.181 was mailed August 06, 2025. The petition was dismissed based on the finding that lack of unity finding in the restriction of July 17, 2024 was reasonable. Thus, the lack of unity finding in the restriction of July 17, 2024 is maintained in its entirety.
Claims 1-2, 4-5, 9-10, and 12-24 are pending.
Newly submitted claims 22-24 are directed to an invention that is independent or distinct from the invention originally claimed and examined for the following reasons: The originally examined claims were drawn to a method of diagnosing hepatocellular carcinoma, however the new claims are drawn to diagnostic a kit and a method treating hepatocellular carcinoma.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 22-24 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
3. Claims 10, 12 and 22-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
4. Claims 1, 2, 4, 5, 9, and 13-21 are currently under consideration.
Rejections Maintained
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.
5. Claims 1, 2, 4, 5, 9, and 13-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract, mental correlation of a natural law/phenomenon without significantly more. The claim(s) recite(s) diagnosing an hepatocellular carcinoma from the determination of the overexpression of the ADAMTSL5 gene, which is an abstract, mental correlation of the overexpression of the ADAMTSL5 gene with the presence of hepatocellular carcinoma. This judicial exception is not integrated into a practical application because the claims generally link the natural law/ phenomenon, the overexpression of the ADAMTSL5 gene, to particular technological environment or field of use, i.e., diagnosing an hepatocellular carcinoma. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims determine the overexpression of the ADAMTSL5 gene at a high level of generality and/or use methods of detection, i.e. immunostaining, that were well-understood, purely conventional or routine in art.
A claim that focuses on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Patents cannot be obtained on subject matter identified by the courts as being exempted from eligibility (i.e., laws of nature, natural phenomenon, and abstract ideas).
The Mayo framework provides that first whether the claims at issue are directed to a patent-ineligible concept is determined. If the answer is yes, then the elements of each claim both individually and “as an ordered combination” are considered to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. The second step—known as the “inventive concept”—requires that claims include elements which would render the method both new and useful.
The recent Eligibility Guidance (2014 Interim Guidance on Patent Subject Matter Eligibility (Interim Eligibility Guidance and 2018 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on January 7, 2019) address the subject matter eligibility analysis for all claims (i.e., machine, composition of matter, manufacture and process claims). The analysis is to be used for evaluating whether a claim is drawn to patent-eligible subject matter.
Step 1 determines whether the claim is directed to a process, machine, manufacture, or composition of matter. If the claim is directed to a statutory category, proceed to Step 2.
Step 2 is the two-part analysis for claims directed to laws of nature, natural phenomena, and abstract ideas (the judicially recognized exceptions).
In Step 2A, determine whether the claim is directed to a law of nature, a natural phenomenon, or an abstract idea (judicial exceptions). “Directed to” means the exception is recited in the claim, i.e., the claim sets forth or describes the exception.
In Prong One of Step 2A it is determined if the claim recites a judicial exception. If the claim recites a judicial exception then Prong Two of Step 2A determines whether the claims recites additional elements that integrate the exception into a practical application.
If the answer to Prong Two of Step 2A is no, Step 2B is used to determine whether the claim as a whole amounts to significantly more than the exception by the recitation of additional elements.
The present claims are directed to a process so Step 1 is satisfied.
For Prong One of Step 2A the claims recite a judicial exception. In particular, the claims recite diagnosing an hepatocellular carcinoma from the determination of the overexpression of the ADAMTSL5 gene, which is an abstract, mental correlation of the overexpression of the ADAMTSL5 gene with the presence of hepatocellular carcinoma. So the answer to Prong One of Step 2A is yes the claims do recite a judicial exception.
For Prong Two of Step 2A the claims do not integrate the exception into a practical application. The judicial exception is not integrated into a practical application because the claims generally link the natural law/ phenomenon, the overexpression of the ADAMTSL5 gene, to particular technological environment or field of use, i.e. diagnosing hepatocellular carcinoma. So the answer to Prong Two of Step 2A is no.
With respect to Step 2B MPEP 2106.05 (I) teaches that
While abstract ideas, natural phenomena, and laws of nature are not eligible for patenting by themselves, claims that integrate these exceptions into an inventive concept are thereby transformed into patent-eligible inventions. Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347, 2354, 110 USPQ2d 1976, 1981 (2014) (citing Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71-72, 101 USPQ2d 1961, 1966 (2012)). Thus, the second part of the Alice/Mayo test is often referred to as a search for an inventive concept. Id.
An inventive concept "cannot be furnished by the unpatentable law of nature (or natural
phenomenon or abstract idea) itself." Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). See also Alice Corp., 134 S. Ct. at 2355, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 78, 101 USPQ2d at 1968 (after determining that a claim is directed to a judicial exception, "we then ask, ‘[w]hat else is there in the claims before us?") (emphasis added)); RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"). Instead, an "inventive concept" is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself. Alice Corp., 134 S. Ct. at 2355, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966
With respect to Step 2B MPEP 2106.05 (d) teaches that:
Another consideration when determining whether a claim recites significantly more than a judicial exception is whether the additional element(s) are well-understood, routine, conventional activities previously known to the industry. If the additional element (or combination of elements) is a specific limitation other than what is well-understood, routine and conventional in the field, for instance because it is an unconventional step that confines the claim to a particular useful application of the judicial exception, then this consideration favors eligibility. If, however, the additional element (or combination of elements) is no more than well-understood, routine, conventional activities previously known to the industry, which is recited at a high level of generality, then this consideration does not favor eligibility.
On the other hand, Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 67, 101 USPQ2d 1961, 1964 (2010) provides an example of additional elements that were not an inventive concept because they were merely well-understood, routine, conventional activity previously known to the industry, which were not by themselves sufficient to transform a judicial exception into a patent eligible invention. Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 79-80, 101 USPQ2d 1969 (2012) (citing Parker v. Flook, 437 U.S. 584, 590, 198 USPQ 193, 199 (1978) (the additional elements were "well known" and, thus, did not amount to a patentable application of the mathematical formula)). In Mayo, the claims at issue recited naturally occurring correlations (the relationships between the concentration in the blood of certain thiopurine metabolites and the likelihood that a drug dosage will be ineffective or induce harmful side effects) along with additional elements including telling a doctor to measure thiopurine metabolite levels in the blood using any known process. 566 U.S. at 77-79, 101 USPQ2d at 1967-68. The Court found this additional step of measuring metabolite levels to be well-understood, routine, conventional activity already engaged in by the scientific community because scientists "routinely measured metabolites as part of their investigations into the relationships between metabolite levels and efficacy and toxicity of thiopurine compounds." 566 U.S. at 79, 101 USPQ2d at 1968. Even when considered in combination with the other additional elements, the step of measuring metabolite levels did not amount to an inventive concept, and thus the claims in Mayo were not eligible. 566 U.S. at 79-80, 101 USPQ2d at 1968-69.
Additionally MPEP 2106.05(d)(II) teaches that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
With respect to the instant claims. the claims perform the well-understood, routine, conventional activity of determining the overexpression of the ADAMTSL5 gene at a high level of generality or with conventional immunological detection methods. In particular, Hornbeck et al. (Current Protocols in Mol. Biol. Enzyme-Linked Immunosorbent Assays (ELISA) 2000, 11.2.1-11.2.22) teach the conventional protocols for ELISAs which uses labeled and unlabeled antibodies for protein detection. See entire document. Hornbeck et al teach that ELISAs have become the system of choice because of their sensitivity, long shelf life of reagents, ease of preparation, and speed and reproducibility of the assays. See Commentary-11.2.19. Additionally, Donaldson JG (Current Protocols in Cell Biology 2015, 4.3.1-4.3.7) teaches conventional immunofluorescence staining protocols with antibodies labeled with fluorescent dyes. See entire article. Donaldson teaches that the use of fluorescently labeled antibodies to localize proteins in cells occurred around 1961. See Commentary-p. 4.3.4.
Thus, given the above, the instant claims do not "practically apply" the naturally occurring phenomena of the overexpression of the ADAMTSL5 gene and its correlation with the presence or absence of hepatocellular carcinoma; rather, the claims "simply inform" to one performing routine active method steps of the phenomena of the overexpression of the ADAMTSL5 gene and its correlation with the presence or absence of hepatocellular carcinoma. The claims do not amount to significantly more than the natural phenomena and thus, as a whole, the claims do not recite something significantly different than a judicial exception(s) and are not patent eligible.
Response to Arguments
6. Applicant argues that the present claim 1 recites wherein the ADAMTSL5 protein levels in the biological sample are measured by using immunostaining.
Applicant argues that as shown in the experimental report in the present application, detection is comparatively easier with immunostaining, notably as compared to immunofluorescence (see page 15, lines 10- 17 and Figs. 2(A) and (B)).
Applicant argues that specifically, as illustrated on Figs. 2(A) and (B), detection by immunostaining offers a significantly improved visual contrast, as opposed to immunofluorescence, which in turn significantly facilitates and improves detection quality.
Applicant argues that accordingly, the present claim 1 is not directed to an observation of a natural phenomenon, but it is directed to the selection of immunostaining as a measurement method, which was non- conventional for detection of overexpression ADAMTSL5 levels in a diagnostic method. See, e.g., Rapid Litig. Mgmt. v. CellzDirect, 827 F.3d 1042, 1051, 119 USPQ2d 1370, 1375 (Fed. Cir. 2016) (process reciting combination of individually well-known freezing and thawing steps was “far from routine and conventional” and thus eligible). Here, similarly as in Rapid, the present inventors have developed a method of determining overexpression of ADAMTSL5S gene in the biological sample by measuring the ADAMTSL5 protein levels in the biological sample using immunostaining, so as to significantly facilitate and improve detection quality.
Applicant argues that in summary, the non-conventional selection of immunostaining constitutes a “practical application” that defines patent-eligible subject matter at step 1 (USPTO step 2A), or to the least, an “inventive concept” beyond the idea of observing ADAMTSL5 overexpression so as to define patent-eligible subject matter at step 2 (USPTO step 2B) of the Mayo/Alice patent-eligibility test (see MPEP 2106.05(1)(A)(iii): “adding unconventional steps that confine the claim to a particular useful application”).
Applicant’s arguments have been considered, but have not been found persuasive. Although the method of claim 1 has been amended to include measurement ADAMTSL5, immunostaining detection of protection proteins is routine and well known method as shown by the teachings of Donaldson as previously set forth and above. Additionally, the courts have recognized that determining the level of a biomarker in blood by any means as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality). See MPEP 2106.05(d)(II) and, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017).
In regard to Applicant’s argument that, as illustrated on Figs. 2(A) and (B), detection by immunostaining offers a significantly improved visual contrast, as opposed to immunofluorescence, which in turn significantly facilitates and improves detection quality, it is noted that immunostaining includes immunofluorescence, see e.g., claims 17-21, and immunofluorescence is a type of immunostaining method. See Ramos-Vara (Veterinary Pathology July 2005, 42 (4): 405-426), i.e. p. 405-left col. and p. 414-left column, 3rd and 4th paragraphs. Thus, the claims encompass methods that are not improved by the claimed technique as argued by Applicant. Additionally, Figs. 2(A) and (B) simply demonstrate ADAMTSL5 mRNA expression levels (Fig. 2A) and detection of ADAMTSL5 protein levels by immunofluorescence and immunostaining. There is no quantitative or qualitative evidence that immunostaining improves detection quality compared to immunofluorescence. Thus, Applicant’s arguments are not found persuasive and the rejection is maintained for the reasons of record.
Applicant makes additional argument with respect to new claim 24 and a treatment method. However, claim 24 is withdrawn and thus the arguments are moot with respect to the invention under examination.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
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.
7. Claim 9 is 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.
Amended claim 9 recites the limitation "the method according to claim 1, where the ADAMTSL5 mRNA levels . . ." in lines 1-2. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite ADAMTSL5 mRNA levels.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
8. Claims 4, 5, and 14-21 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 is drawn to the method according to claim 3, wherein the ADAMTSL5 protein levels in the biological sample are measured by adding at least one antibody anti-ADAMTSL5 type to the biological sample. Amended claim 1 is now drawn to measuring the ADAMTSL5 protein levels by using immunostaining. Thus, claim 4 fails to further limit the subject matter of the claim upon which it depends and fails to include all the limitations of claim 1.
Claim 5 depends from claim 4 and thus is also rejected.
Claim 14 is drawn to the method according to claim 2, wherein the overexpression of ADAMTSL5 gene in the biological sample is determined by measuring the ADAMTSL5 protein levels or mRNA levels in the biological sample. Claim 2 depends from amended claim 1. Amended claim 1 is now drawn to measuring the overexpression of the ADAMTSL5 gene by measuring the ADAMTSL5 protein levels by using immunostaining. Thus, claim 14 fails to further limit the subject matter of the claim upon which it depends and fails to include all the limitations of claim 1. Claims 15 and 16 depend from claim 14 and thus are also rejected.
Claims 17-21 depend from claims 4 and 14 and ultimately depend from amened claim 1. Claims 17-21 are drawn to “wherein the ADAMTSL5 protein levels in the biological sample are measured by using immunostaining”. Amended claim 1 is now drawn to measuring the overexpression of the ADAMTSL5 gene by measuring the ADAMTSL5 protein levels by using immunostaining. Thus, claims 17-21, with respect to the immunostaining alternative, fail to further limit the subject matter of the claim upon which they depend.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
9. All other objections and rejections recited in the Office Action of November 20, 2024 are withdrawn in view of Applicant’s amendments and arguments
10. No claims allowed.
11. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached on M-F 8:30-5:30 Eastern Time
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet L Epps-Smith can be reached on 571-272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Peter J Reddig/
Primary Examiner, Art Unit 1642