DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s election of (i) AID, (ii) G>A mutations in GYW motifs at MC-2 sites, and (iii) and breast cancer in the reply filed on August 14, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-20 are currently pending.
Claims 8 and 11-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 14, 2026.
Duplicate Claim Warning
3. Applicant is advised that should claim 6 be found allowable, claim 7 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 101
4. 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 1-7, 9-10, 15-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judical exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature.
The claims recite a correlation between targeted somatic mutagenesis and cancer (see clm 15). This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas.
Claim 1 recites the following steps:
“analyzing the sequence of the at least one nucleic acid molecule to determine, for a plurality of mutations of a mutation type at one or more motifs recognized or targeted by the mutagenic agent, the codon context of those mutations to thereby identify the location of a mutation and mutation type for each of a plurality of mutated codons in the at least one nucleic acid molecule, wherein the mutagenic agent is activation-induced cytidine deaminase (AID) and wherein the codon context of an individual mutation is determined by determining at which of the three positions of a corresponding mutated codon the individual mutation occurs” and
“determining that targeted somatic mutagenesis is likely to have occurred when there is a higher than expected percentage or number of mutations of a mutation type at one of the three positions in the plurality of mutated codons”.
The analyzing and determining steps, as drafted, are a process that under its broadest reasonable interpretation, covers performance of the limitations in the mind but for the recitation of generic computer components. That is, other than reciting “in a processing system” nothing in the claim precludes these steps from practically being performed in the human mind. For example, but for the “in a processing system” language, the claim encompasses the user reading the sequence of a nucleic acid in a laboratory report and thinking about the mutation type, codon context, and whether or not target somatic mutagenesis occurred. These limitations are a mental process.
Claim 15 recites the following steps:
“detecting in the sequence of the at least one nucleic acid molecule, for a plurality of mutations, the mutation type and the codon context of an individual mutation, wherein the codon context of an individual mutation is determined by determining at which of the three positions of a corresponding mutated codon the individual mutation occurs, wherein the mutations are at one or more motifs recognized or targeted by activation-induced cytidine deaminase (AID)”
“detecting the occurrence of targeted somatic mutagenesis, wherein targeted somatic mutagenesis has occurred when there is a higher than expected percentage or number of mutations of a mutation type at one of three positions in a codon in a plurality of mutated codons”
“determining that the subject is likely to have or to develop cancer when targeted somatic mutagenesis has occurred”
The detecting/detecting/determining steps, as drafted, are a process that under its broadest reasonable interpretation, covers performance of the limitations in the mind but for the recitation of generic computer components. That is, other than reciting “in a processing system” nothing in the claim precludes these steps from practically being performed in the human mind. For example, but for the “in a processing system” language, the claim encompasses the user reading the sequence of a nucleic acid in a laboratory report and thinking about the mutation type, codon context, whether or not target somatic mutagenesis occurred, and whether the subject is at risk of having cancer. These limitations are a mental process.
Claim 17 recites the following steps:
“analyzing the sequence of a nucleic acid molecule to identify somatic mutations of a mutation type known to be associated with the mutagenic agent”;
“determining the codon context of the mutations to identify the preferred nucleotide position at which the mutations occur at a higher than expected frequency”; and
“identifying the nucleotides flanking the mutations at the preferred nucleotide position so as to identify a motif that is common to the mutations”.
The analyzing/determining/identifying steps, as drafted, are a process that under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation of generic computer components. That is, other than reciting “in a processing system” nothing in the claim precludes these steps from practically being performed in the human mind. For example, but for the “in a processing system” language, the claim encompasses the user reading the sequence of a nucleic acid in a laboratory report and thinking about the mutation codon context and the nucleic acids that flank the mutations. These limitations are a mental process.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Only claim 15 recites steps in addition to the judicial exceptions. Claim 15 recites obtaining at least one nucleic acid molecule from a biological sample from a subject and determining the sequence of the at least one nucleic acid molecule. These steps are not considered to integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
Only claim 15 recites steps in addition to the judicial exceptions. Claim 15 recites obtaining at least one nucleic acid molecule from a biological sample from a subject and determining the sequence of the at least one nucleic acid molecule. These steps do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art to the judicial exceptions.
The steps are recited at a high level of generality. Obtaining a nucleic acid molecule from a biological sample in order to perform tests is well understood, routine, and conventional activity for those in the field of molecular based diagnostics. Further nucleic acid sequencing is well understood, routine, and conventional activity for those in the field of molecular based diagnostics.
Additionally the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches the following:
[0096] Any method known in the art for obtaining and assessing the sequence of a nucleic acid molecule can be used in the methods of the present invention.
Further it is noted 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.
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);
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);
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);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
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)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
4. 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.
Claim 10 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 pre-AIA the applicant regards as the invention.
Claim 10 is rejected over the recitation of the phrase “wherein the mutagenic agent is AID if the number or percentage of…”. In view of the recitation of “if” it implies that claim 1 requires determining what the mutagenic agent is. However this is not recited in claim 1. It is unclear if the claim requires determining what the mutagenetic agent is or if this information is already known by the person performing the claimed method steps. Clarification is required.
Claim Rejections - 35 USC § 112(a)
5. 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 1-10, and 15-16 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.
Breadth of the Claims/Nature of the Invention:
Claim 20 is drawn to a method for determining the likelihood that targeted somatic mutagenesis by AID has occurred.
Claim 15 is drawn to a method for determining the likelihood that a subject has or will develop cancer based on the occurrence of targeted somatic mutagenesis by AID.
In view of the recitation of “subject” the claims encompass both human and non-human subjects. In view of the recitation of “cancer” the claims broadly encompass ANY cancer. Only claim 16 is limited to breast cancer. The claims recite the analysis of at least one nucleic acid molecule. The nucleic acid molecule can be a portion of a gene, a full gene, multiple genes, a whole chromosome etc. The nucleic acid molecule can also be any length (i.e., 10mer, 100mer, 1000mer, 10,000mer, etc.). Further the nucleic acid molecule can be obtained from any sample type (i.e., blood, urine, tumor tissue, non-tumor tissue, etc.)
The claims require detecting a plurality of somatic mutations that occur at one or more motifs targeted by AID. The claims do not set forth the motifs that are targeted by AID and this information is necessary to practice the claimed method. The claims broadly encompass detecting somatic mutations at any motif including each of the motifs set forth in claim 9. Only claim 10 sets forth specific motifs that are targeted by AID i.e., GYW, WA, and WRC.
Once the somatic mutations occurring at the motifs are identified, the claims require determining the mutation types. The claims do not set forth the mutation types that are caused by AID and this information is necessary to practice the claimed method. The claims broadly encompass detecting ANY mutation type including each of the mutation types set forth in claim 9. Only claim 10 sets forth the mutation types that are targeted by AID i.e., G > A mutations in GYW motifs, A > G mutations in WA motifs, and C > T mutations in WRC motifs.
Once the somatic mutations occurring the motifs are identified and mutation type is determined the claims require determining the codon context of the mutation. The claims do not set forth the codon context of mutations that are caused by AID and this information is critical to practicing the claimed method. The claims broadly encompass detecting mutations at any codon position (MC-1, MC-2, MC-3). Only claim 10 sets forth the codon context of mutations that are targeted by AID i.e., G > A mutations in GYW motifs at MC-2 sites, A > G mutations in WA motifs at MC-2 sites, and C > T mutations in WRC motifs at MC-1 sites.
The claims state that targeted somatic mutagenesis is likely to have occurred when there is a higher than expected percentage of number of mutations of a mutation type at one of the three positions in the plurality of mutated codons. However the claims do not set forth how the expected percentage is calculated.
The claims state that a subject is likely to have or develop cancer when targeted somatic mutagenesis by AID has occurred.
The nature of the invention requires a reliable correlation between the presence of targeted somatic mutagenesis and cancer. In order to determine if targeted somatic mutagenesis has occurred from exposure to AID, the skilled artisan must know the motifs targeted by AID, the mutation types that occur in these motifs, and the codon context of the mutations.
Teachings in the Specification
The specification (para 0006) teaches that the present invention is predicated in part on the determination that there is a bias towards somatic mutagenesis by various mutagenic agents at motifs when the motifs are present in a particular codon context within the nucleic acid molecule. Thus, while it was previously understood that some mutagenic agents target motifs, as described herein mutagenesis at these motifs occurs predominantly when the motifs are within a particular codon context, a process termed herein targeted somatic mutagenesis. By identifying this additional requirement for the codon context of the motif, the present inventors have developed methods for determining the likelihood that this type of targeted somatic mutagenesis has occurred, and the likelihood that one or more particular mutagenic agents are the cause of the targeted somatic mutagenesis.
The specification (para 0012) teaches that a determination that an AID-associated mutation process is a likely cause of targeted somatic mutagenesis is made if the number or percentage of observed A>G mutations in WA motifs at MC-2 sites, G>A mutations in GYW motifs at MC-2 sites, or C>T mutations in WRC motifs at MC-1 sites, in the non-transcribed strand of the nucleic acid molecule is higher than expected.
The specification (Example 1) describes the analysis of TP53 somatic mutations in breast cancer. The frequency and context of somatic mutations in the TP53 gene in breast cancers was assessed by accessing the IARC TP53 database and extracting data specific for breast cancer. The number of point mutations in this dataset was large (N=2,514). The sequences of the cDNA transcripts were analyzed and using these transcripts, the sequence context around each mutation was analyzed for mutations at the AID motif (GYW/WRC), APOBEC1 motif (TG/CA) and APOBEC3G motif (CG/CG). The mutations were assessed in relation to their positions in a mutated codon. The codon context and frequency of each of the 2,514 somatic mutations in the TP53 gene from the pooled breast cancer dataset is shown in Table 1. Table 2 shows the codon context of the 2514 somatic mutations for the TP53 breast cancer dataset occurring at AID, APOBEC1 and APOBEC3G motifs. As shown below, for GYW motifs linked to AID activity, 185/200 (92.5%) of all G>A transitions occurred at an MC-2 site, and 185/248 (74.6%) of all mutations at GYW sites (i.e. G>A/C/T) were G>A transitions at an MC-2 site. In contrast, at WRC sites, 106/132 (80.3%) of all C>T transitions occurred at an MC-1 site, and 106/168 (63.1%) of all mutations of C (i.e. C>A/G/T) were C>T transitions at an MC-1 site. Further for the A>G transitions at WA sites, 128/141 (90.8%) occurred at an MC-2 site, and 128/167 (76.6%) of all mutations of A at WA sites (i.e. A>C/G/T) were G>A transitions at an MC-2 site. As an elevated level of A>G mutations at WA sites are recognized as a characteristic feature of SHM activity and diagnostic of the involvement of an RNA template intermediate, this finding supports a prediction that endogenous AID-initiated mutation processes are active in at least many of the samples in the dataset.
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The specification (Example 2) further describes how the codon bias patterns observed for mutation at the AID, APOBEC 1, and APOBEC3G motifs were used to generate "rules" or diagnostic criteria for use in predicting whether targeted somatic mutation of a nucleic acid molecule is occurring as a result of AID, APOBEC1 and/or APOBEC3G activity. A higher than expected number of G>A mutations off the GYW (AID) motif at MC-2 sites is associated with AID deaminase activity on the transcribed strand. A higher than expected number of C>T mutations off the WRC (AID) motif at MC-1 sites is associated with AID deaminase activity on the non-transcribed strand. A higher than expected number of A>G mutations off the WA motif at MC-2 is an indication of AID-linked mutation processes and thus AID activity. When applying these rules, it is assumed that the set of mutations of each nucleotide are independent of each other, and that if the mutagenic agents are not present, the distributions of mutations off each nucleotide in each of the codon sites MC-1 and MC-2 will be randomly distributed for mutations of A, G, C, or T.
FIG. 2 shows an example of how the diagnostic criteria can be used to determine the probability that the codon-bias mutation distribution arose by chance or by targeted somatic mutation by AID or APOBEC3G. For each of the above selected diagnostic categories, the number of Observed (O) and the Expected (E) mutations are tabulated in Table form. For each of the diagnostic categories, the number of Expected (E) mutations is calculated using the total number of mutations likely to arise across MC-1 and MC-2 sites for each of the 3 possible types of mutation off a particular nucleotide if the mutations are random.
As shown in FIG 3, in regards to the WRC motif that is associated with AID activity resulting in mutations of cytosine (C) off the non-transcribed strand, if the number of mutations at C were randomly distributed, the mutations would be evenly distributed across the MC-1/MC-2 sites and across C>A, C>G and C>T (C>A/G/T). Thus, in this example the Expected (E) number of C>T mutations at an MC-1 site is the total number of observed C>A/T/G mutations at MC-1 and MC-2 sites (i.e. 1+1+72+6+1+1), divided by the number of possible types/positions of mutations (i.e. 6), which equals 13.67. Referring again to FIG. 3, the higher than expected number of G>A mutations off the GYW motif at MC-2 sites and higher than expected number of C>T mutations off the WRC motif at MC-1 sites indicates AID deaminase activity, while the higher than expected number of G>A mutations off the CG motif at MC-2 sites and higher than expected number of C>T mutations off the CG motif at MC-1 sites indicates APOBEC3G activity.
The specification (Example 3) teaches the analysis of TP53 somatic mutations in various other cancers. The data is presented in Figures 4-11 showing that several cancers with TP53 mutations are associated with AID and APOBEC deaminase activity.
The specification (Example 4) teaches the analysis of PIK3CA somatic mutations in breast cancer tissue and TET2 in hematopoietic and lymphoid tissue. The data is presented in Figures 12-13 showing that mutations are associated with AID and APOBEC deaminase activity.
The specification (Examples 5 and 6) teaches the analysis of whole exomes from samples from subjects with adenoid cystic carcinoma and prostate cancer.
The Predictability or Unpredictability of the Art:
While the state of the art with regard to the detection of somatic mutations is high, the unpredictability of correlating the presence of somatic mutations with a particular phenotype (such as cancer) is even higher. The unpredictability is discussed below.
In the instant case the claims require detecting whether somatic mutagenesis has occurred and if so it is then determined that the subject is likely to have or develop cancer. However just because somatic mutagenesis is present does not mean that a subject is likely to have or develop cancer. Martincorena (Science Vol 349 Issue 6255 9/25/2015 pages 1483-1489) teaches that spontaneously occurring mutations accumulate in somatic cells throughout a person’s lifetime and that most of the somatic mutations that steadily accumulate in our cells are harmless (abstract, page 1483, col 1). Martincorena teaches that of the many thousands of mutations that cancer genomes have, typically only a handful are driver mutations (disease causing mutations). Thus it is highly unpredictable if the claimed method can be used to determine whether or not a subject has cancer or an increased risk of cancer.
In the instant case the claims require determining if targeted somatic mutagenesis by a AID has occurred wherein the occurrence of targeted somatic mutagenesis indicates that the subject is likely to have or develop cancer. The claims state that targeted somatic mutagenesis has occurred when there is a higher than expected percentage or number of mutations of a mutation type at one of three positions in a codon in a plurality of mutated codons in a nucleic acid molecule in a biological sample taken from the subject. The claims broadly encompass looking at mutations in a nucleic acid molecule of a biological sample. The nucleic acid molecule could be a 100,000 mer, 1000 mer, 100 mer, 10 mer. In the instant case determining which nucleic acid molecule to even examine when determining if targeted somatic mutagenesis has occurred is highly unpredictable. Martincorena (Science Vol 349 Issue 6255 9/25/2015 pages 1483-1489) discloses the frequency of somatic mutations in 198 cancer genomes across 20 tissues (Fig 2). Only three genes are mutated in more than 10% of patients across the range of tumor types shown here TP53 (36.1%), PIK3CA (14.3), and BRAF (10%) (page 1486). This is especially relevant to point out because based on Figure 2 it appears that the genes that have somatic mutations in one type of cancer are different than the genes that have somatic mutations in other types of cancer. Based on the teachings in Fig 2 it is highly unpredictable if one could determine if a subject has breast cancer based on the detection of somatic mutations in the CTNNB1, CUX1, CYLD, DAXX, or DDX5 genes because these genes are not known to have somatic mutations in breast cancer. Thus it appears that selecting the appropriate nucleic acid molecule to analyze is critical to being able to detect targeted somatic mutagenesis and thereby diagnose a particular type of cancer. In other words, the sequences that would need to be analyzed to detect targeted mutagenesis that causes breast cancer are going to be different that the sequences that one would need to be analyze to detect targeted mutagenesis that causes glioblastoma, thyroid cancer, melanoma, or any other cancer. The specification (para 162) teaches that targeted somatic mutagenesis occurs in the TP53 gene in breast cancer, cervical cancer (all types), cervical adenocarcinoma, colon adenocarcinoma, hepatocellular carcinoma, pancreatic cancer, prostate cancer, and malignant melanoma. However the specification is silent with respect to which other nucleic acid sequences should be analyzed for targeted somatic mutagenesis caused by AID with respect to each of these different cancers. Here the disclosure of a single gene (TP53) in which targeted somatic mutagenesis occurs in for breast cancer, cervical cancer (all types), cervical adenocarcinoma, colon adenocarcinoma, hepatocellular carcinoma, pancreatic cancer, prostate cancer, and malignant melanoma does not provide any adequate basis to support the generic claims which encompass diagnosing these cancers based on the analysis of any “nucleic acid molecule”. Further just because targeted somatic mutagenesis occurs in the TP53 gene in breast cancer, cervical cancer (all types), cervical adenocarcinoma, colon adenocarcinoma, hepatocellular carcinoma, pancreatic cancer, prostate cancer, and malignant melanoma, it does not mean that it will occur in the TP53 gene of ANY cancer. One of skill in the art cannot immediately envision which cancers will and which cancers will not have targeted somatic mutagenesis in the TP53 gene caused by AID. Further one of skill in the art cannot immediately envision which other genes will have targeted somatic mutagenesis caused by AID in any one cancer.
Further it is highly unpredictable if it is possible to determine that a subject has ANY type of cancer by analyzing a nucleic acid sequence for somatic mutations, wherein the nucleic acid sequence is from ANY biological sample (blood, breast tissue, urine, lung tissue, hair, etc.). In the instant case it is highly unpredictable if somatic mutations that are present is breast tumor tissue will also be present in other types of samples (blood, hair, urine, lung tissue, etc.) obtained from the same subject. There are no showings in the specification that all of the cells throughout a subject with breast cancer will have the somatic mutations that are present in a sample of the subject’s breast tumor tissue. Thus it appears that the biological sample being analyzed is dependent on the type of cancer that one is attempting to diagnose yet the claims are much broader.
In order to practice the claimed invention which requires determining if targeted somatic mutagenesis by AID has occurred, the user of the method must know in advance the mutation type, motif, and codon context that is targeted by AID. The specification (para 0012) teaches that a determination that an AID-associated mutation process is a likely cause of targeted somatic mutagenesis is made if the number or percentage of observed A>G mutations in WA motifs at MC-2 sites, G>A mutations in GYW motifs at MC-2 sites, or C>T mutations in WRC motifs at MC-1 sites, in the non-transcribed strand of the nucleic acid molecule is higher than expected. However independent claims 20 and 34 are much broader because they encompass ANY mutation type, ANY motif, and ANY codon context. This breadth is not supported by the teachings in the specification. It is unclear if additional mutation types, motifs, and codon contexts could be indicative of AID.
Further, it is highly unpredictable as to whether the results obtained with human subjects in the specification could be extrapolated to non-human subjects. Knowledge that AID targets certain motifs, nucleotide types, and codon positions in the human genome does not allow on to conclude AID will also be present in non-human subjects and target the same motifs, nucleotide types, and codon positions in those subjects. The specification does not teach homologs of the AID family members in a representative number of different non-human subjects. The specification also does not provide any evidence that targeted somatic mutagenesis even occurs in a representative number of different non-human subjects and leads to cancer in those subjects. Relevant to the elected species (AID) the Gene Card for AID (found online at https://www.genecards.org/cgi-bin/carddisp.pl?gene=AICDA discloses 47 different species where no ortholog for AID could be found. Those species include: African clawed frog (Xenopus laevis), fruit fly (Drosophila melanogaster), Honey Bee (Apis mellifera), oranguatn (Pongo pygmaeus), pig (Sus scrofa), and zebrafish (Danio rerio). As such it is unpredictable as to whether AID is present in a representative number of non-human subjects and will causes targeted somatic mutagenesis in those subjects which leads to cancer.
Degree of Experimentation:
For the reasons discussed above, it would have required undue, unpredictableexperimentation of a trial- and-error nature to practice the recited methods in the full, broad scope encompassed by the rejected claims. The type of experimentation requiredis not routine and the subsequent data analysis is sophisticated. Furthermore, theoutcome of the tasks is entirely unpredictable based on the limited data and analysisprovided in the instant specification.
Conclusions:
Taking into consideration the factors outlined above, including the nature of theinvention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue amount of experimentation would be required to make and use the invention.
Claim Rejections - 35 USC § 102
6. The following is a quotation of the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 17-20 are rejected under pre-AIA 35 U.S.C. 102b as being anticipated by Gil (Molecular Immunology 44 (2007) 494-505).
Regarding Claim 17 Gil teaches that EBV-transformed lymphoblastoid cell lines express the activation-induced cytidine deaminase (AID) gene. The question of whether AID activation induces the process of somatic hypermutation (SHM) was investigated in adult-derived LCLs. It was found that the VH gene from the rheumatoid factor-producing RF LCL (derived from a rheumatoid arthritis patient), accumulated somatic point mutations in culture. Overall, nine unique mutations have accumulated in the rearranged VH gene since the generation of the RF cell line. Gil teaches that the mutations were preferentially targeted to the DGYW motifs and showed preference for CG nucleotides, indicating that they were AID-mediated (abstract). Gil teaches that they performed DNA sequencing on RT-PCR reaction products. The results were analyzed and compared to the NCBI database using the Blastn and IgBlast software (page 496 col 1-col 2). The results are shown in Fig 5 and Table 1 partially reproduced below. Gil teaches that the nine clonal somatic mutations found in the RF VH when compared to its germline counterpart were generated either in vivo in a normal memory B cell from which the transformed RF cell line originated or in vitro following the EBV-transformation. Similar to the unique mutations generated in vitro, the clonal mutations are CG-biased (i.e., 89%) and are preferentially targeted to the WRCH/DGYW hotspot motifs (∼3.7-fold), supporting the possibility that at least some of the latter mutations may have been generated in vitro following EBV transformation (page 503, col 2).
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Thus Gil teaches a method comprising in a processing system (the computer that the BLAST and IgBLAST alignments were performed on) analyzing the sequence of a nucleic acid molecule to identify somatic mutations of a mutation type (CG nucleotides) known to be associated with the mutagenic agent AID; determining the codon context of the mutations to identify the preferred nucleotide position at which the mutations occur at a higher than expected frequency (See Table 1 where most mutations were in the second position of the codon); and identifying the nucleotides flanking the mutations at the preferred nucleotide position (see Fig 5) so as to identify a motif that is common to the mutations (WRCH/DGYW).
Regarding Claim 18 Gil teaches the following mutation types: C>T, G>T, G>A, G>C, and A>G.
Regarding Claim 19 Gil teaches that most of the mutations occurred in nucleotide position MC-2 which is the second position of the codon (see mutations 5-9).
Regarding Claim 20 Gil teaches that analysis of the 13 mutations generated during cell culture (i.e., the six mutations found in the present work and the seven detected in the VH sequence of the 1992 RF cell culture) shows that these mutations were preferentially targeted to the WRCH and its complement DGYW hotspot motifs (i.e., 4/12 mutations which were observed versus 39/383 which is the expected ratio of the number of hotspot motifs divided by the number of all the possible four-nucleotide motifs. This results in an observed/expected ratio of ∼3.3).
Improper Markush Grouping
7. Claims 1-7, 9, 15-16 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush groupings of: a mutagenic agent selected from the group consisting of aflatoxin, AID, and a APOBEC cytidine deaminase (which encompasses 11 APOBEC family members) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 706.03(y) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 706.03(y)IIA).
Herein, the recited alternative species do not share a single structural similarity, as each mutagenic agent has a different chemical structure. Accordingly, while the different mutagenetic agents are asserted to have the property of being mutagenic, they do not share a substantial structural similarity essential to this activity.
Further, the recited mutagenic agents do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that they will behave in the same manner and can be substituted for one another with the same intended result achieved. In the present situation there is no expectation from the knowledge in the art that each of the recited mutagenic agents will behave in the same way in the context of the claimed invention. For example the recited mutagenic agents are not considered to be an recognized class because the prior art does not teach that it was well known that each of the recited mutagenic agents could be substituted for each other with the expectation that the same intended result would be achieved.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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