Last week, the U.S. Patent and Trademark Office issued U.S. Patent No. 8,628,920, which is entitled "Method for early diagnosis of liver cancer and prediction of metastasis." The '920 patent, which is assigned to National Tsing Hua University in Taiwan, contains claims to a method of determining the risk of liver cancer and metastasis.
The inventors demonstrated that alpha-mannosidase RNA expression levels, specifically MAN1A1, MAN1A2 and MAN1B1, in liver tissue obtained from hepatitis B virus positive liver cancer patients were approximately double the levels of control liver tissue, with increased RNA expression levels correlating with a more advanced cancer stage. Interestingly, MAN1C1 RNA expression levels in stage I or II liver cancer patients were approximately half the level than that in normal liver tissue.
A review of the file history of the '920 patent indicates that the Examiner issued a rejection of the claims under 35 U.S.C. § 101 in a non-final Office Action mailed December 4, 2012 for being drawn to a non-statutory method for having a "natural principal" as a limiting step without reciting additional steps that integrate the natural principal into the claimed invention. The Examiner asserted that the "natural principal" constituted the levels of MAN1A1, MAN1A2, MAN1B1, MAN1C1, and MMP9 in samples from a subject as compared to controls are indicative of risk of liver metastasis. The Examiner stated that, according to Mayo v. Prometheus, a claim that focuses on use of a natural principal must also include additional elements or steps to show that the inventors have practically applied, and added something significant, to the natural principal itself.
As originally filed, claim 6 of the '920 patent recited:
6. A method for diagnosis of liver metastasis, comprising the steps of:
(A) providing a sample obtained from a subject;
(B) assessing the expression level of four subtypes of a-mannosidase genes consisting of MAN1A1, MAN1A2, MAN1B1 and MAN1C1 in the sample;
(C) comparing MAN1A1, MAN1A2, MAN1B1 and MAN1C1 expression level in the sample with those in a normal control; and
(D) determining whether the subject having a risk of liver metastasis in accordance with the result of step (C);
wherein while the MAN1A1, MAN1A2 and MAN1B1 expression levels in the sample are higher than those in the normal control, and the MAN1C1 expression level in the sample is lower than that of the normal control, such that the subject is determined to have a risk of liver metastasis.
In response to the § 101 rejection, the Applicant amended claim 6 to add limitations of "specific markers" to detect and assess and compare the expression level by the "specific markers." Furthermore, the Applicant asserted that claim 6 must be performed using the substantial "specific markers" and thus, the claim amounts to significantly more than a natural principal itself.
In Applicant's response filed on April 8, 2013, claim 6 was amended as follows:
6. (Currently amended) A method for diagnosis determining risk of liver metastasis metastatic liver cancer, comprising the steps of:
(A) providing a sample obtained from a subject;
(B) assessing the RNA expression level of four subtypes of a-mannosidase genes consisting of MAN1A1, MAN1A2, MAN1B1 and MAN1C1 in the sample by detecting with one or a plurality of specific markers;
(C) comparing the specific markers of MAN1A1, MAN1A2, MAN1B1 and MAN1C1 expression level in the sample with those in a normal control; and
(D) determining whether the subject having has a risk of liver metastasis of liver cancer in accordance with the result of step (C);
wherein a subject with while the MAN1A1, MAN1A2 and MAN1B1 expression levels in the sample that are higher than those in the normal control, and [[the]] MAN1C1 expression level in the sample that is lower than that of the normal control, such that the subject is determined to have indicates the subject has a high risk of liver metastasis of liver cancer,
wherein the sample and the normal control are liver biopsy or blood sample.
In the next and final Office Action mailed May 29, 2013, the Examiner withdrew the § 101 rejection without comment, but issued a rejection under 35 U.S.C. § 112, second paragraph, for the unclear recitation of "markers" in claim 6. In order to expedite prosecution, the Examiner proposed amendments to claim 6 that removed the "specific markers" amendment made by the Applicant. In a response to the final Office Action filed in August of 2013, the Applicant amended claim 6 (which issued as claim 1 in the '920 patent) to include the Examiner's recommended amendment to remove the recitation of "specific markers." The application was allowed in September.
Claim 1 of the '920 patent recites:
Claim 1. A method for determining risk of metastatic liver cancer, comprising the steps of:
(A) providing a sample obtained from a subject;
(B) assessing the RNA expression level of four subtypes of alpha-mannosidase genes consisting of MAN1A1, MAN1A2, MAN1B1 and MAN1C1 in the sample by detecting MAN1A1, MAN1A2, MAN1B1 and MAN1C1 RNA expression levels in the sample;
(C) comparing the MAN1A1, MAN1A2, MAN1B1 and MAN1C1 expression levels in the sample with MAN1A1, MAN1A2, MAN1B1 and MAN1C1 expression levels in a normal control; and
(D) determining whether the subject has a risk of metastasis of liver cancer in accordance with the result of step (C);
wherein a subject with MAN1A1, MAN1A2 and MAN1B1 expression levels in the sample that are higher than those in the normal control, and MAN1C1 expression level in the sample that is lower than that of the normal control has a high risk of metastasis of liver cancer, wherein the sample and the normal control are liver biopsies.
