DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Application, Amendments and/or Claims
Claims 1-20, drawn to a method for detecting an increased risk of developing late stage progression of cancer in a subject (and in a subject undergoing treatment) comprising measuring the level of wildtype Siglec-XII in a sample containing epithelial cells from the subject contacting the sample with an antibody that specifically binds to wildtype Siglec-XII, are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 08 April 2024) was received and complies with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. It has been placed in the application file and the information referred to therein has been considered as to the merits.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (an abstract idea and a law of nature) without significantly more.
The claims recite a method for detecting an increased risk of developing late stage progression of cancer in a subject (and in a subject undergoing treatment) comprising measuring the level of wildtype Siglec-XII in a sample containing epithelial cells from the subject contacting the sample with an antibody that specifically binds to wildtype Siglec-XII comparing the measured level of the bound antibody to a reference level, wherein an elevated level of wildtype Siglec-XII expression in the subject (or in the subject undergoing treatment for cancer) is indicative of an increased risk in developing late stage progression of cancer.
STEP 1: Are the claims directed to a process, machine, manufacture or composition of matter? YES. The instant claims are directed to a process.
STEP 2A (The Judicial Exception) PRONG ONE: Do the claims recite a law of nature, a natural phenomenon (i.e. product of nature) or an abstract ideal? Yes, the instant claims are directed to an abstract idea and a law of nature.
The instant claims are directed to an abstract ideal for the following reasons:
The claims recite the step
"..comparing the measured level of the bound antibody to a reference level..” (see claims 1 and 14)
“..as compared to expression level in a corresponding normal sample..” (see claims 9 and 18).
The "comparing" step can be performed using mental steps or basic thinking, representing an abstract idea. Limitations such as comparing, assessing, determining, is a process that, under its broadest reasonable interpretation, covers performance of the limitation in the mind. The claim falls within the “Mental Processes” as it involves evaluating and judging. Accordingly, the claim recites an abstract ideal (see Univ. of Utah Research Found V. Ambry Genetics Corp., 113 USPQ2d 1241 (Fed. Cir. 2014)).
The instant claims are directed to a law of nature for the following reasons:
The claims recite a naturally occurring correlation between the amount of Siglec-12 expression and the risk of developing late stage progression of cancer in a subject (and in a subject undergoing treatment).
Accordingly, the claims recite a Law of Nature similar to the naturally occurring correlation found to be law of nature by the Supreme Court in Mayo Collaborative Services V. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012) (see also, Cleveland Clinic Foundation V. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017);; Ariosa Diagnostics, Inc. V. Sequenom, 788 F.3d 1371,1373, 115 USPQ2d 1152, 1153 (Fed. Cir. 2015)).
STEP 2A PRONG TWO: Do the claims recite additional elements that integrate the exception into a practical application of the exception? NO.
Obtaining a sample from a subject in order to perform tests is a well-understood, routine, conventional activity previously engaged in by scientists in the field of diagnostics, and this step is recited at a high level of generality such that it amounts to insignificant pre-solution activity (e.g., obtaining samples is a necessary precursor to gather data for using the correlation). There is no meaningful limitation in this step that distinguishes it from well-understood, routine and conventional data gathering activity engaged in by scientists prior to Applicant's invention at the time of filing.
The state of the art at the time of filing the instant application teaches obtaining samples containing epithelial cells from subjects.
See wherein Park et al. teach obtaining tissue samples from individuals who underwent gastrectomy for gastric cancer. Epithelial tissues from the cancerous tissue and adjacent normal tissue from each specimen were arrayed into a paraffin block to create a tissue microarray (TMA). Park et al. teach immunostaining was performed on the TMA using an anti-CXCL5 antibody. Park et al. teach to measure serum CXCL5 levels by ELISA, serum samples were collected from patients with gastric cancer and from patients with benign conditions such as gastritis and hyperplastic polyp (pages 836-837). Park et al. teach CXCL5 overexpression was associated with late stage gastric cancer (Discussion, pages 838-839)(Park et al. CXCL5 overexpression is associated with late stage gastric cancer. J Cancer Res Clin Oncol 133:835–840; 2007).
STEP 2B: Do the claims provide an inventive concept i.e. does the claim recite additional element(s) or a combination of additional elements that amount to significantly more than the judicial exception in the claim? NO.
A method of using an antibody to contact a sample with the antibody that specifically binds to a protein in order to measure protein expression in samples obtain from subjects are routine and well-established. As was stated above, Park et al. teach using an anti-CXCL5 antibody to measure CXCL5.
See also Mitra et al. who teach using anti-Siglec-XII monoclonal antibody 1130 and anti-Siglec-XII monoclonal antibody 276 to measure Siglec-X11 protein expression in samples containing epithelial cells from subjects (Reference submitted by Applicant; Mitra et al. Journal of Biological Chemistry Volume 286/26:23003; July 2011)..
Additionally, it is noted that claims 14-20 do not teach a specific treatment step.
Claim 1 recites that the subject is undergoing treatment.
Claim 2 recites “..further comprising administering an additional cancer therapy to the subject having an elevated level of wild type Siglec-XII expression..”
Claim 3 recites, “..the method of claim 2, wherein the additional cancer therapy comprises a complex comprising a monoclonal antibody and a toxin, and administration of the complex results in the death of cells expressing wild type Siglec-XII, thereby treating cancer in the subject.”
However, the treatment is recited at a very general level. For example, the broad claims fail to recite a particular type of cancer that is to be treated and/or a particular cancer therapy or antibody/toxin complex to be administered.
Instant claim 6 recites skin cancer, colorectal cancer or prostate cancer. Nonetheless, treatments for these types of cancers were routine in the art.
For example, Ockrim et al. teach oral estrogens were an effective treatment for prostate cancer but were abandoned because of an increased risk of cardiovascular toxicity and particularly thromboembolism. Ockrim et al. teach that transdermal estradiol produces an effective tumor response and negligible cardiovascular toxicity (Ockrim et al. Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism. ABSTRACT. Journal of Urology, Volume 174, Number 2, pp. 527-533, 2005).
There are no meaningful limitations that distinguishes the claimed method from well-understood and conventional data gathering engaged by scientist. There is nothing unconventional or non-routine regarding the steps of measuring protein markers in a sample. Determining whether wild type Siglec-XII is overexpressed in a sample merely instructs a scientist to use a detection technique with an antibody to discern protein levels.
In conclusion, the claimed invention is directed to a judicial exception without significantly more. The claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately. The claims essentially set forth a law of nature with generalized instructions to apply it.
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.
Claims 1-20 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 14 are indefinite because of the acronym “Siglec-XII”, which has not been defined in the claims. Acronyms should be defined upon their first use in a claim. The presence of an undefined acronym renders a claim indefinite. Claims 2-13 and 15-20 are included in this rejection insofar as they depend from claim 1 or 14 and/or do not resolve the issue discussed above.
Claims 7 and 17 are indefinite because of the limitations “anti-Siglec-XII monoclonal antibody 1130” and “anti-Siglec-XII monoclonal antibody 276”.
The use of the laboratory designation “anti-Siglec-XII monoclonal antibody 1130” and “anti-Siglec-XII monoclonal antibody 276” as the sole means of identifying the antibodies renders the claims indefinite because different laboratories may use the same laboratory designations to define completely distinct antibodies.
It is suggested that this issue could be remedied by amending the claims to include the depository accession number of a cell line producing the antibodies. This is because deposit accession numbers are unique identifiers that unambiguously define a given cell line and the antibody that is produced thereby.
Alternatively, this rejection can also be remedied by reciting the specific amino acid sequences of the variable heavy (VH) chain and the variable light (VL) chain for each antibody or the specific amino acid sequences of the 6 complementarity derived regions (CDRs) for each antibody. The metes and bounds of the instant claims cannot be determined.
Claims 12, 13, 15 and 16 are indefinite because of the recitations “..wherein the reference level is 0” and “wherein the measured level of the bound antibody is greater than 0”.
It is unclear what is meant by “0”; (i.e. for example, does 0 mean 0 picograms, 0 mgs, does this pertain to protein, DNA, RNA, etc.). Further, the specification does not teach this limitation and does not provide a standard for measuring the scope of the term (see MPEP 2173.05(b)(IV)). The metes and bounds of these claims cannot be determined.
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 1-20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The instant specification teaches that the present invention relates to the detection and analysis of Siglec-XII in a human biological sample for risk prediction, prognostication and diagnosis of disease.
The specification teaches that in two stage IV colorectal cancer cohorts FIRE3 (592 patients from Germany and Austria) and TRIBE (508 patients from Italy), greater than 80% of patients expressed SIGLEC12 based on the frameshift mutation (FIGS. 2C and 2D). This specification teaches that in FIRE3 the overall survival increased from 28 months to 51 months between Siglec-XII expressers and non-expressers (FIGS. 2E and 2F). The specification teaches a correlation between Siglec-XII expression and poor prognosis in late stage colorectal cancer (para 0090).
The instant claims are not enabled for the following reasons:
1. The specification fails to demonstrate detecting an increased risk of developing late stage progression of any cancer in a subject undergoing treatment comprising measuring the level of wildtype Siglec-XII in a sample containing epithelial cells from the subject wherein an elevated level of wild type Siglec-XII expression in the subject undergoing treatment for cancer is indicative of an increased risk in developing late stage progression of cancer.
The specification only teaches late stage colorectal carcinoma patients undergoing treatment wherein an elevated level of wildtype Siglec-XII expression was detected.
Cancer encompasses vastly different types of pathologies and etiologies. See wherein Hassanpour et al. teach that cancer in the broader sense refers to more than 277 different types of cancer disease. Hassanpour et al. teach that cancer is a variety disease at the tissue level. Hassanpour et al. teach that this variety is a major challenge for its specific diagnosis, followed by efficacy of treatment. Hassanpour et al. teach scientists have stated several gene mutations are involved in cancer pathogenesis; also included are chemical compounds, environmental chemical substances with carcinogenic properties, viruses, bacteria and radiation rays (Hassanpou et al. Review of cancer from perspective of molecular. Journal of Cancer Research and Practice. Volume 4:127-129; available July 2017).
It would be highly unpredictable that an increased risk of developing late stage progression of any cancer in a subject undergoing treatment could be detected by measuring the level of wildtype Siglec-XII from the subject’s sample.
2. Chemotherapeutic/cancer drugs affect the body in various ways. There is no evidence that wildtype Siglec-XII expression levels could be detected in a saliva sample or urine sample from a subject undergoing cancer treatment, wherein an elevated level of wildtype Siglec-XII expression in said subject undergoing treatment for cancer is indicative of an increased risk in developing late stage progression of cancer and the instant specification fails to teach such.
3. The specification fails to teach a method for detecting an increased risk of developing late stage progression of any cancer in a subject wherein an elevated level of wild type Siglec-XII expression in the subject is indicative of an increased risk in developing late stage progression of cancer (see claims 14-20).
It is noted that the subject population in these claims encompass subjects who do not have cancer and are not undergoing cancer treatment.
A very high degree of evidence is required over an extended period of time that an increased risk of developing late stage progression of any cancer in a subject (who does not have cancer and is not undergoing treatments) can be detected wherein an elevated level of wild type Siglec-XII expression in said subject’s sample is indicative of an increased risk in developing late stage progression of cancer. In addition, the instant specification actually teaches no correlation between Siglec-XII and carcinoma risk (see Examples 3 and 4).
The subject population in these claims also encompass subjects who have cancer and are not undergoing cancer treatment.
It is noted that in very early stages of some prostate cancers, subjects may not require cancer treatment and opt for a prostatectomy, which removes part or all of the prostate gland.
The instant specification actually teaches no clear correlation of Siglec-XII status with progression of early stage prostate carcinomas. The specification teaches most of these cases were originally diagnosed by measuring prostate specific antigen (PSA), which picks up many early stage cases that never progress in the lifetime of the individual. The specification teaches the patients with a poor outcome were compared to those with no evidence of disease recurrence following prostatectomy (NED), it was observed that most of the patients (84 out of 122) detected by PSA screening did not have disease progression at the time of follow up (see Example 3).
4. Lastly, the claimed methods require an antibody that specifically binds to wildtype Siglec-XII to measure the level of wildtype Siglec-XII in a subject’s sample in order to determine an increased risk of developing late stage progression of cancer in a subject (or in a subject undergoing treatment). The instant specification employs biological materials anti-Siglec-XII monoclonal antibody 1130 and anti-Siglec-XII monoclonal antibody 276.
The instant specification teaches that a mouse monoclonal antibody against Human Siglec-XII—A fusion protein Siglec-XII-Fc including the first three Ig-like domains of human Siglec-XII and the human IgG Fc domain was prepared. The fusion protein was used to immunize mice to generate monoclonal antibodies (BD Pharmingen). Two final clones, 1130 and 276 were obtained. Specificity was confirmed by lack of cross-reactivity with Siglec-7-Fc. Studies were done using a mixture of the two clones or clone 276 or 1130 alone (see para 0073).
However, it is unclear whether the antibodies are readily available to the public, are deposited or are reproducible wherein when reproduced, the antibodies have the exact structure and chemical identity, as the anti-Siglec-XII monoclonal antibody 1130 and anti-Siglec-XII monoclonal antibody 276 taught in the specification.
MPEP 2411.01 teaches: Rejections Based on Deposit Issue [R-07.2015]
Under 37 CFR 1.809(a), once the Examiner has determined that access to a biological material is necessary, and there is no information that would support the conclusion that access is currently available in accordance with these regulations, the Examiner should make an appropriate rejection under 35 U.S.C. 112 until such time as a deposit in accordance with these regulations is actually made or a written assurance is received in the patent application that such a deposit will be made upon an indication of allowability of the application.
The Examiner should clearly indicate the statutory basis for the rejection and the reasons that are relied upon by the Examiner to conclude that the application does not comply with some requirement of 35 U.S.C. 112. Although not exhaustive, the following grounds of rejection may be applicable in appropriate circumstances:
(A) 35 U.S.C. 112(a), enablement requirement. Rejection for lack of an enabling disclosure without access to a specific biological material. This ground of rejection should be accompanied by evidence of scientific reasoning to support the conclusion that a person skilled in the art could not make or use the invention defined in and commensurate with the claims without access to the specific biological material.
Since the biological materials are essential to the claimed invention they must be obtainable by a repeatable method set forth in the specification or otherwise readily available to the public. A person skilled in the art could not make or use the invention defined in and commensurate with the claims without access to the specific biological material. If the biological materials are not so obtainable or available, the requirements of 35 U.S.C. § 112 may be satisfied by a deposit of the biological materials. The specification does not disclose a repeatable process to obtain the biological materials, and it is not apparent if the biological materials are readily available to the public.
If the deposit is made under the Budapest Treaty, then an affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the specific biological materials have been deposited under the Budapest Treaty and that the biological materials will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein.
If the deposit has not been made under the Budapest Treaty, then in order to certify that the deposit meets the criteria set forth in 37 C.F.R. §§ 1.801-1.809, Applicant may provide assurance of compliance by an affidavit or declaration, or by a statement by an attorney of record over his or her signature and registration number, showing that:
(a) during the pendency of this application, access to the invention will be afforded to the Commissioner upon request;
(b) all restrictions upon availability to the public will be irrevocably removed upon granting of the patent;
(c) the deposit will be maintained in a public depository for a period of 30 years or 5 years after the last request or for the effective life of the patent, whichever is longer;
(d) a test of the viability of the biological material at the time of deposit will be made (see 37 C.F.R. § 1.807); and
(e) the deposit will be replaced if it should ever become inviable.
Applicant’s attention is directed to M.P.E.P. §2400 in general, and specifically to §2411.05, as well as to 37 C.F.R. § 1.809(d), wherein it is set forth that “the specification shall contain the accession number for the deposit, the date of the deposit, the name and address of the depository, and a description of the deposited material sufficient to specifically identify it and to permit examination.” The specification should be amended to include this information; however, Applicant is cautioned to avoid the entry of new matter into the specification by adding any other information. Finally, Applicant is advised that the address for the ATCC has recently changed, and that the new address should appear in the specification. The new address is:
American Type Culture Collection
10801 University Boulevard
Manassas, VA 20110-2209
Due to the inherent unpredictability and the large quantity of experimentation necessary to detect an increased risk of developing late stage progression of any cancer in a subject undergoing treatment comprising measuring the level of wildtype Siglec-XII; the inherent unpredictability and the large quantity of experimentation necessary to detect an increased risk of developing late stage progression of any cancer in a subject who does not have cancer (or in a subject who has cancer and is not undergoing treatment) comprising measuring the level of wildtype Siglec-XII; the large quantity of experimentation necessary make antibodies with the exact structure and chemistry of anti-Siglec-XII monoclonal antibody 1130 and anti-Siglec-XII monoclonal antibody 276 and screen said antibodies for the biological function of specifically binding wildtype Siglec-XII in a sample and detecting an increased risk of developing last stage progression of cancer; the lack of direction/guidance presented in the specification regarding same; the absence of working examples regarding same; the complex nature of the invention; and state of the art which teaches cancer encompasses vastly different types of pathologies and etiologies and that cancer in the broader sense refers to more than 277 different types of cancer disease; undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5-7, 14 and 17 are rejected under 35 U.S.C. 102(a1) as being anticipated by Do et al. (Reference submitted by Applicant; Polymorphic Pseudogenization of SIGLEC12 in Humans: Relationship to Late Stage Cancer Progression. UC San Diego; 2017).
Do et al. teach antibodies anti-Siglec-XII monoclonal antibody 1130 and anti-Siglec-XII monoclonal antibody 276 (page 4)(applies to claims 7 and 17). Do et al. teach the use of anti-Siglec-XII monoclonal antibody 1130 and anti-Siglec-XII monoclonal antibody 276 to discern expression of Siglec-12 in cancerous and non-cancerous tissue (page 4). Do e al. teach Siglec-XII expression is higher in human carcinomas than in normal human tissues (pages 13-14). Do et al. teach analyzing overall survival of late stage colorectal carcinoma patients participating in a phase 3 drug trial. The patients were being treated with FOLFOXIRI plus either bevacizumab or cetuximab)(applies to claims 2 and 3). Do et al. teach that 83% of the late stage colorectal carcinoma patients expressed the wildtype Siglec-XII (page 20).
Do et al. teach that Siglec-XII expression is correlated with a significantly increased rate of late stage colorectal carcinoma (abstract and page 20)(applies to claims 1, 5 and 6). It is noted that claim 14 encompasses subjects who have cancer and are not undergoing cancer treatment AND subjects who have cancer and are undergoing treatment (applies to claim 14).
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 9/15/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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