BitLaw

Example 31: Screening For Gene Alterations

The following illustrates an exemplary analysis using the 2014 IEG for actual claim 1 and hypothetical claims 70, 75, 80, and 85 modeled after the technology in U.S. Patent 5,753,441. Actual claim 1 was held ineligible by the Federal Circuit as directed to an abstract idea without additional elements that amount to significantly more than the abstract idea in Association for Molecular Pathology v. U.S. Patent and Trademark Office, 689 F.3d 1303 (Fed. Cir. 2012) (“Myriad CAFC”), aff’d in part and rev’d in part on other grounds, Association for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107 (2013). (It is noted that claims 7 and 8 of the same patent were held ineligible in University of Utah Research Foundation v. Ambry Genetics Corp., 774 F.3d 755 (Fed. Cir. 2014).) Hypothetical claims 70 and 80 are eligible in Step 2B, because they recite specific and unconventional ways of gathering data that amount to significantly more than the abstract idea, e.g., amplifying nucleic acids via a hypothetical technique known as “Cool-Melt PCR.” Hypothetical claims 75 and 85 are eligible in Step 2A, because they are not directed to any judicial exception.

Background

Applicant discovered the “wild-type” sequence of the human BRCA1 gene (i.e., the typical sequence of the gene in humans), and has also discovered naturally occurring alterations from the wild-type sequence that are correlated with an increased likelihood of developing breast or ovarian cancer. Applicant’s disclosure provides methods of screening patients for alterations in the BRCA1 gene by comparing a patient’s BRCA1 sequence with the wild-type BRCA1 sequence. The compared sequences can be germline (genomic) DNA sequences, RNA sequences, or cDNA sequences.

At the time the invention was made and the application was filed, scientists routinely compared DNA sequences using two data-gathering techniques. The first technique seeks to hybridize two different DNA molecules (e.g., a probe and DNA isolated from a patient sample), and detects whether the molecules bind to each other and form a hybridization product. The second technique amplifies (makes copies of) at least part of a DNA molecule such as DNA isolated from a patient sample, by using a set of primers to produce amplified nucleic acids, and then sequences the amplified nucleic acids. The probes and primers used in these techniques are short single-stranded DNA molecules that typically have a naturally occurring nucleotide sequence, for example a probe to the BRCA1 gene may have a nucleotide sequence that is identical to a portion of the germline sequence of the wild- type BRCA1 gene.

In one embodiment, applicant discloses using a computer-implemented micromechanical method known as Scanning Near-field Optical Microscopy (SNOM) to detect hybridization of a single probe to its target. SNOM is a technique that achieves high spatial resolution of a nanometric sample, using a laser and optical microscope that are controlled by a computer. At the time the invention was made and the application was filed, the use of SNOM to study DNA hybridization had been discussed in several articles in widely-read scientific journals. However, scientists were not commonly or routinely using SNOM to study DNA hybridization at the time the invention was made and the application was filed. Instead, scientists at the time typically used autoradiography to detect hybridization products.

In another embodiment, applicant discloses using Cool-Melt polymerase chain reaction (Cool-Melt PCR) to amplify BRCA1 DNA from the patient sample. Cool-Melt PCR uses lower melting and annealing temperatures than conventional PCR. Because these lower temperatures result in preferential amplification of mutant nucleic acids as compared to wild-type nucleic acids, Cool-Melt PCR has a 20-fold higher sensitivity of mutation detection than conventional PCR. At the time the invention was made and the application was filed, Cool-Melt PCR was known and used by a few scientists in the field. Several years after filing the application, Cool-Melt PCR became a standard laboratory technique that appeared in virtually every laboratory manual and was conventionally used by most scientists in the field to amplify mutant nucleic acids.

Claims

1. A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject.

70. The method of claim 1,

wherein said comparing BRCA1 sequences further comprises: hybridizing a wild-type probe to a BRCA1 gene isolated from said sample; and
detecting the presence of a hybridization product by measuring conformational changes in the probe that are indicative of hybridization to the BRCA1 gene with scanning near-field optical microscopy.

75. A method for hybridizing BRCA1 sequences comprising:

hybridizing a wild-type probe to a BRCA1 gene isolated from a tissue sample from a human subject; and
detecting the presence of a hybridization product by measuring conformational changes in the probe that are indicative of hybridization to the BRCA1 gene with scanning near-field optical microscopy.

80. The method of claim 1, wherein said comparing BRCA1 sequences further comprises:

amplifying by Cool-Melt PCR all or part of a BRCA1 gene from said sample using a set of primers to produce amplified nucleic acids; and
sequencing the amplified nucleic acids.

85. A method for amplifying BRCA1 sequences comprising:

amplifying by Cool-Melt PCR all or part of a BRCA1 gene from a tissue sample from a human subject using a set of primers to produce amplified nucleic acids; and
sequencing the amplified nucleic acids.

Analysis

Claim 1: Ineligible.

The claim recites a step or act, i.e., comparing the patient’s genetic sequence with wild type genetic sequences. Thus, the claim is directed to a process, which is one of the statutory categories of invention (Step 1: YES).

The claim is then analyzed to determine whether it is directed to any judicial exception. The claim recites a step of comparing the patient’s BRCA1 sequence with wild-type BRCA1 sequences, and a wherein clause stating the result of the comparison, which is that a difference in the compared sequences indicates that the patient has an alteration in the BRCA1 gene. This step of comparing is recited at a high level of generality that merely requires a comparison of two pieces of information and imposes no limits on how the comparison is performed. In Myriad CAFC, the court found this step of comparing to be an abstract idea.

When applying the 2014 IEG and interpreting the claim during examination, it is apparent that the step of comparing could be performed by a human using mental steps or basic critical thinking. Similar mental processes have been held by the courts to be abstract ideas, e.g., collecting and comparing known information in Classen, or comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC. The specific information that is being compared (sequences of a BRCA1 gene, BRCA1 RNA, or BRCA1 cDNA with wild-type sequences) merely narrows the abstract idea, which does not make the comparison step less abstract and is not sufficient to provide eligibility on its own. Thus, the claim is directed to an abstract idea (Step 2A: YES).

Note that although nature-based product limitations are recited in the claim (e.g., genes), analysis of the claim as a whole indicates that this claim is focused on a process of comparing information about the products, and is not focused on the products per se. Thus, there is no need to perform the markedly different characteristics analysis on the recited nature-based product limitations in this claim.

Next, the claim as a whole is analyzed to determine whether any additional element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the abstract idea. The claim recites a single step of comparing, along with a wherein clause, all of which were identified as the abstract idea explained above. There are no other elements/steps recited in the claim. Accordingly, the claim as a whole does not amount to significantly more than the abstract idea of comparing information (Step 2B: NO). The claim is not patent eligible.

A rejection of claim 1 should identify the exception by pointing to the comparison of sequences in the claim and explain that this type of comparison of information has been held by the courts to be an abstract idea and that limits on the type of information being compared merely narrow the abstract idea. The rejection should also identify that there are no additional elements/steps in the claim. For clarity, the rejection can explain why the wherein clause does not impose any additional limitations on the claimed method, but merely breathes meaning into the comparison step by stating the result of the comparison.

Claim 70: Eligible

Claim 70 depends from claim 1 and recites at least one step or act, e.g., comparing the patient’s genetic sequence with wild type genetic sequences. Thus, the claim is directed to a statutory category of invention (a process; Step 1: YES). As a dependent claim, claim 70 incorporates the comparing step of claim 1, which as explained above is an abstract idea. Therefore, the claim is directed to a judicial exception (Step 2A: YES).

Next, the claim as a whole is analyzed to determine whether any additional element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception. Claim 70 recites two additional elements, i.e., that the comparing of claim 1 further comprises a hybridizing step and a detecting step.

The step of hybridizing a wild-type probe to a BRCA1 gene isolated from a sample is recited at a high level of generality, and merely instructs a scientist performing the process to use any hybridization techniques with any probe that she wishes to use to detect any alteration. When recited at this high level of generality, there is nothing in this step that distinguishes it from well-understood, routine and conventional activity engaged in by scientists at the time the invention was made and the application was filed. While this step specifies that the compared sequences are of a probe and a gene, limiting the comparison in this way imposes no limits on how the comparison is performed. Further, it is well established that the mere physical or tangible nature of additional elements such as the hybridizing step does not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347, 2358-59 (2014)). Thus, taken alone, the hybridizing step does not amount to significantly more.

Claim 70, however, further recites a detecting step in which conformational changes in the gene probe that are indicative of hybridization with the patient’s BRCA1 gene are measured by scanning near-field optical microscopy (SNOM). Although SNOM was known to scientists at the time the invention was made and the application was filed, e.g., because it had been discussed in several widely-read scientific journals, mere knowledge of this technique does not make the use of SNOM to detect DNA hybridization routine or conventional in this field. Instead, the evaluation turns on whether the use of SNOM to detect DNA hybridization was actually routinely or conventionally used by scientists at the time the invention was made and the application was filed. Because it was not, the recitation of SNOM to detect DNA hybridization distinguishes claim 70 from well-understood, routine and conventional methods of detecting DNA hybridization such as autoradiography. Thus, the claim’s recitation of using SNOM is more than a mere instruction to “apply” the abstract idea using well- understood, routine or conventional techniques in the field. Whether taken alone or as a combination with the other additional elements, the recitation of detecting hybridization using SNOM yields a claim as a whole that is significantly more than the judicial exception itself (Step 2B: YES). The claim recites patent eligible subject matter.

If the examiner believes that the record would benefit from clarification, remarks could be added to an Office action or reasons for allowance indicating that the claim recites the abstract idea of comparing sequence information. However, the claim is eligible because it recites additional limitations that when considered as a combination are more than a mere instruction to “apply” the abstract idea using well-understood, routine or conventional techniques in the field.

Claim 75: Eligible

Claim 75 recites at least one step or act, e.g., hybridizing a wild-type probe to a BRCA1 gene isolated from a sample. Thus, the claim is directed to a statutory category of invention (a process; Step 1: YES).

The claim is then analyzed to determine whether it is directed to any judicial exception. The claim recites a step of hybridizing a wild-type probe to a BRCA1 gene isolated from a sample and a detecting step in which conformational changes in the gene probe that are indicative of hybridization with the patient’s BRCA1 gene are measured by scanning near-field optical microscopy (SNOM). These steps do not recite or describe any recognized exception. See, e.g., Mayo Collaborative Svcs. v. Prometheus Labs., 566 U.S. , 132 S. Ct. 1289, 1297 (2012) (recited steps of administering a drug to a patient and determining the resultant level of 6-thioguanine in the patient “are not themselves natural laws”). Accordingly, the claim is not directed to an exception (Step 2A: NO), and is eligible.

Note that although nature-based product limitations are recited in the claim (e.g., the probe and BRCA1 gene), analysis of the claim as a whole indicates that the claim is focused on a process of detecting whether the probe has hybridized to the BRCA1 gene, and is not focused on the products per se. Thus, there is no need to perform the markedly different characteristics analysis on the recited nature-based product limitations. In addition, note that because the analysis of this claim ends with eligibility at Step 2A, the Step 2B analysis does not need to be performed. Thus, the examiner would not need to evaluate the significantly more considerations for this claim.

If the examiner believes that the record would benefit from clarification, remarks could be added to an Office action or reasons for allowance, indicating that the claim is not directed to any judicial exception.

Claim 80: Eligible

Claim 80 depends from claim 1 and recites at least one step or act, e.g., comparing the patient’s genetic sequence with wild type genetic sequences. Thus, the claim is directed to a statutory category of invention (a process; Step 1: YES). As a dependent claim, claim 80 incorporates the comparing step of claim 1, which as explained above is an abstract idea. Therefore, the claim is directed to a judicial exception (Step 2A: YES).

Next, the claim as a whole is analyzed to determine whether any additional element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception. Claim 80 recites two additional elements, i.e., that the comparing of claim 1 further comprises an amplifying by Cool-Melt PCR step, and a sequencing step.

The step of sequencing the amplified nucleic acids is recited at a high level of generality, and merely instructs a scientist performing the process to use any sequencing technique that she wishes to use. When recited at this high level of generality, there is nothing in this step that distinguishes it from well-understood, routine and conventional activities previously engaged in by scientists in the field at the time the invention was made and the application was filed. Further, it is well established that the mere physical or tangible nature of an additional element such as the sequencing step does not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp., 134 S.Ct. at 2358-59).

Claim 80, however, further recites a step in which Cool-Melt PCR is used to amplify the patient’s BRCA1 gene. Although Cool-Melt PCR was used by a few scientists in the field to amplify nucleic acids at the time the invention was made and the application was filed, use by only a few scientists does not make the technique routine or conventional in the field as a whole. Nor does it matter that at a later time, Cool-Melt PCR became a routine and conventional technique. Instead, the evaluation turns on whether the use of Cool-Melt PCR to amplify nucleic acids was actually routinely or conventionally used by scientists in this field at the time the invention was made and the application was filed. Because it was not, the recitation of amplification using Cool-Melt PCR distinguishes claim 80 from well-understood, routine and conventional methods of amplification such as standard PCR. Thus, the claim’s recitation of amplifying nucleic acids using Cool-Melt PCR is more than a mere instruction to “apply” the abstract idea using well-understood, routine or conventional techniques in the field. Whether taken alone or as a combination with the other additional elements, the recitation of amplifying using Cool-Melt PCR yields a claim as a whole that is significantly more than the judicial exception itself (Step 2B: YES). The claim recites patent eligible subject matter.

If the examiner believes that the record would benefit from clarification, remarks could be added to an Office action or reasons for allowance indicating that the claim recites the abstract idea of comparing sequence information. However, the claim is eligible because it recites additional limitations that when considered as a combination are more than a mere instruction to “apply” the abstract idea using well-understood, routine or conventional techniques in the field.

Claim 85: Eligible

Claim 85 recites at least one step or act, e.g., amplifying nucleic acids using Cool-Melt PCR. Thus, the claim is directed to a statutory category of invention (a process; Step 1: YES).

The claim is then analyzed to determine whether it is directed to any judicial exception. The claim recites a step of amplifying nucleic acids (all or part of a human subject’s BRCA1 gene) using Cool- Melt PCR and a step of sequencing the amplified nucleic acids. These steps do not recite or describe any recognized exception. See, e.g., Mayo Collaborative Svcs. v. Prometheus Labs., 566 U.S. , 132 S. Ct. 1289, 1297 (2012) (recited steps of administering a drug to a patient and determining the resultant level of 6-thioguanine in the patient “are not themselves natural laws”). Accordingly, the claim is not directed to an exception (Step 2A: NO), and is eligible.

Note that although nature-based product limitations are recited in the claim (e.g., the primers and BRCA1 gene), analysis of the claim as a whole indicates that the claim is focused on a process of amplifying and sequencing a BRCA1 gene, and is not focused on the products per se. Thus, there is no need to perform the markedly different characteristics analysis on the recited nature-based product limitations. In addition, note that because the analysis of this claim ends with eligibility at Step 2A, the Step 2B analysis does not need to be performed. Thus, the examiner would not need to evaluate the significantly more considerations for this claim.

If the examiner believes that the record would benefit from clarification, remarks could be added to an Office action or reasons for allowance, indicating that the claim is not directed to any judicial exception.