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 .
Election/Restrictions
Applicant's election with traverse of Group I, Lysine-specific demethylase 5A (KDM5A) and Interleukin-18 binding protein (IL18BP) of claim 1 and probes 226367_at and 222868_s_at of claim 2 in the reply filed on 6/27/2025 is acknowledged. The traversal is on the ground(s) that MPEP § 803 provides that "[i]f the search and examination of an entire application can be made without serious burden, the Examiner must examine it on the merits, even though it includes claims to distinct or independent inventions." (Emphasis added.). This is not found persuasive because kit can be use do isolate nucleic acid homologs from different species. Thus the product can has a materially different use than the methods of groups I and III. Further the method of group I requires a sample from a subject, thus has a materially different design , does not overlap in scope and is not an obvious variant of method which encompasses mental steps such as group III. Further the restriction requirement states ,(a) the inventions have acquired a separate status in the art in view of their different classification; (b) the inventions have acquired a separate status in the art due to their recognized divergent subject matter; (c) the inventions require a different field of search (for example, searching different classes/subclasses or electronic resources, or employing different search queries); (d) the prior art applicable to one invention would not likely be applicable to another invention; (e) the inventions are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph. As provided above, the groups require a different field of search, fall into separate classifications, and appear to have a separate status in the art when they are classifiable together; and are likely to raise serious examination issues, such as non-prior art issues under 35 U.S.C. 101, pre-AIA 35 U.S.C. 112, first paragraph and/or 35 U.S.C. 112(a). Further searching one gene will not inherently provide art on another gene or sequence.
Claims 3, 5-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/27/2025.
Priority
The instant application is filed 06/08/2021 and is a continuation in part of 16513230 , filed 07/16/2019, which is is a continuation of 15509044 , filed 03/06/2017, which is a national stage entry of PCT/US2015/049665 with an international filing date: 09/11/2015; which claims priority from provisional application 62049431 , filed 09/12/2014 and claims priority from provisional application 62085922 , filed 12/01/2014.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 19(e), 120, 121, 365(c), or 386(c) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 16513230 , 15509044 , PCT/US2015/049665, 62049431 , 62085922, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Independent claim 1 now recites SEQ ID NO 1-6. However, the priority documents do not have sequence listings and thus do not provide adequate written description for claim 1 and dependent claims. Thus they are being given priority to the instant filing date.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/10/2024 is being considered by the examiner.
The listing of references in the specification, for example pages 10-11, 17-20, is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The incorporation of essential material in the specification by reference to a reference other than an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(f).
The specification on page 36 teaches probe sets and Gene symbols including those recited in claim 1. Further the probes of claim 2 and 3. The specification teaches, “Microarrays: analyses using microarrays technology has been widely adopted for generating gene expression data on a genomic scale. Gene expression profiles were from obtained from Affymetrix UI33plus chips from a previously published study by S. Eschrich, H. Zhang, H. Zhao, D. Boulware, J.-H. Lee, G. Bloom, and J. F. Torres-Roca, "Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform.," Int. J. Radiat. Oncol. Biol. Phys., vol. 75, no. 2, pp. 497-505, October 2009” (pages 24-25).. (page 23)Thus the gene symbols and probes appear to be from an Affymetrix database.
The attempts to incorporate subject matter into this application by reference to the AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195 are ineffective because the databases these Gene symbols reference are not US Patents or published patent applications. The attempt to incorporate subject matter into this application by reference to AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195. Further claim 2 references probes that appear to be from the Affymetrix database 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at is ineffective because incorporation by reference under rule 1.57 requires that the incorporation be expressly presented in the specification to be effective. The rule defines essential and nonessential material. Essential material may be incorporated by reference to US Patents or US Patent Application Publications, but the patent or publication may not itself incorporate such essential material. As the accession number or probe sequences are essential material as they are present in the claim. Finally, the guidance on rule 1.57 incorporation by reference requires that a sequence be uniquely identified. Searching for Hs.441600 did not provide a nucleic acid sequence .
The specification on page36 that recites the “gene symbol” and the probes. However, searching Hs.441600 in genecards, (https://www.genecards.org/Search/Keyword?queryString=hs.441600, downloaded 6/26/2018) or pubmed (https://www.ncbi.nlm.nih.gov/pubmed/?term=hs.441600, downloaded 6/26/2018) did not provide any indication of the sequence(s) required.
Thus while the instant specification provides intent to incorporate by reference by the claiming the accession numbers/gene symbol or probes the sequences is not uniquely identified, absent secondary considerations.
The disclosure is objected to because of the following informalities:
Page 3, line 20 recites, “Error! Reference Source not found.)” This appears to be a typographical error and should be corrected.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required:
Appropriate correction is required.
Claim Objections
Claims 1-2, 4 objected to because of the following informalities:
Claim 1 is objected to as it recites “Chromosome 5 Open Reading Frame 56 (C5orf56), Cystic fibrosis transmembrane conductance regulator (CFTR), Cytoplasmic FM1RfIleracting Protein _I (CYFIP1)”, “ Interleukin-18 binding protein (EL 18BP)”, “Lysine-specific demethylase 5A (KDM5A)”, and “Ras related in brain (RAB) 13 (RAB13).” These are not proper nouns of the first word of the claim and thus do not need to be capitalized.
Claims 2, 4 are objected to as they depend from claim 1.
Improper Markush Group
Claims 1-2, 4 are rejected under the judicially approved ‘‘improper Markush grouping’’ doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch, 631 F.2d 716, 719–20 (CCPA 1980). A Markush claim contains an ‘‘improper Markush grouping’’ if: (1) the species of the Markush group do not share a ‘‘single structural similarity,’’ or (2) the species do not share a common use. 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. However, when the Markush group occurs in a claim reciting a process or a combination (not a single compound), it is sufficient if the members of the group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. See MPEP § 803.02.
Here each species is considered to be a method for predicting radiation sensitivity in a subject by assaying a gene panel. Claim 2 recites oligonucleotide probe sets..
The recited alternative species in the groups set forth here do not share a single structural similarity, as each method relies on detection of different gene or probe. Each gene or probe that could be detected is itself located in a separate region of the genome and has its own structure. The nature of gene or probe to a gene is that they are difference . Each gene or probe to a gene has a unique sequence relative to the others- they are not structurally the same when you consider the sequence required to identify one particular gene relative to another gene. The gene recited in the instant claims, and the methods which detect them, do not share a single structural similarity since each consists of a different nucleotide sequences. The only structural similarity present is that all genes or probes to genes are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with radiation sensitivity. The association between the claimed genes is not considered as ‘property’ as the association is a statistical construct, it is a conclusion based on analysis of a specific population and may not be present in subject outside of the population assayed. Further there is no evidence the association was known in the prior art. While the instant specification asserts genes have a common function of being correlated with the asserted phenotype, the association between the claimed genes is not clear from their very nature. If the instantly claimed genes (or probe to genes). are placed in a group with an equal number of genes (or probe to genes) the skilled artisan could not differentiate those associated with a phenotype from those that are not associated with a phenotype. Thus the one of skill in the art could not identify those genes (or probe to genes) that are asserted to be associated with the phenotype by their very nature. Thus the instant claims have not met the requirements of a proper Markush group.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Claim Rejections - 35 USC § 112
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 1-2 and 4 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of detecting gene expression in a subject comprising:
Obtaining a biological sample from a subject, assaying the expression of KDM5A in the sample and comparing expression to a control sample.
, does not reasonably provide enablement for detection of AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195, generating a radiation sensitivity score or treating based on high or low scores or the probes recited in claim 2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors have been described by the court in re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in the Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
Claim 1 is drawn to A method for predicting radiation sensitivity in a subject, comprising: a) assaying a biological sample from the subject for gene expression levels of a gene panel comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, or more genes selected from the group consisting of AW979276 (MAGP)(SEQ ID NO: 1), Chromosome 5 Open Reading Frame 56 (C5orf56) (SEQ ID NO: 4)), Cystic fibrosis transmembrane conductance regulator (CFTR), Cytoplasmic FMR1 Interacting Protein 1 (CYFIPI), Hs.441600 (AW592246) (SEQ ID NO: 2), Hs.664912 (BF515306) (SEQ ID NO: 5), Hs.668213 (BG150083)(SEQ ID NO: 6), Interleukin-18 binding protein (IL18BP), Lysine-specific demethylase 5A (KDM5A), LOC100129195 (ZSCAN16-AS1)(SEQ ID NO: 3), and Ras related in brain (RAB) 13 (RAB13); b) comparing the gene expression levels to control values to generate a radiation sensitivity score; and c) treating the subject with radiation therapy when the patient has a high radiation sensitivity score and treating the subject without radiation therapy when the patient has a low radiation sensitivity score.
Thus the claims encompass anything that can broadly be identified by the gene symbols of the claim. The gene symbols are essential matter as they are present in the claim.
Further the claims encompass anyway to generate a radiation sensitivity score by any type of comparison.
Claim 2 depends from claim 1 and draws the invention to wherein the biological sample is assayed using a microarray comprising two or more oligonucleotide probe sets selected from the group consisting of 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at.
Thus the claims encompass anything that can broadly be identified by the probe sets of the claim. The probe sets are essential matter as they are present in the claim.
Claim 4 depends from claim 1 and draws the invention to wherein the gene expression levels are analyzed by multivariate regression analysis or principal component analysis to calculate the risk score.
The amount of direction or guidance and the Presence and absence of working examples.
MPEP 608.01 (p)[R-2] states that “While the prior art setting may be mentioned in general terms, the essential novelty, the essence of the invention, must be described in such details, including proportions and techniques, where necessary, as to enable those persons skilled in the art to make and utilize the invention.”
The specification teaches probe sets and Gene symbols including those recited in claims 5 and 2. The specification teaches, “[0144] Microarrays: analyses using microarrays technology has been widely adopted for generating gene expression data on a genomic scale. Gene expression profiles were from obtained from Affymetrix UI33plus chips from a previously published study by S. Eschrich, H. Zhang, H. Zhao, D. Boulware, J.-H. Lee, G. Bloom, and J. F. Torres-Roca, "Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform.," Int. J. Radiat. Oncol. Biol. Phys., vol. 75, no. 2, pp. 497-505, October 2009” (pages 24-25).. Thus the probes are from an Affymetrix database. The HS numbers are from the Ensemble database, while AW979276 and L0C100129195 are Gen Bank accession numbers.
The claims recite “AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195”. Further claim 2 references probes that appear to be from the Affymetrix database 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at”. The recitation of gene symbol or probe identifiers in the claims constitutes an attempt to incorporate by reference to the gene symbol or probe identifiers the subject matter which is contained within the recited database record. This recitation constitutes an improper incorporation by reference of essential material since it is material that is necessary to describe the claimed invention. Essential material may not be incorporated by reference to non-patent publications (MPEP 608.01)(p).
Presence and absence of working examples
The teachings of the specification are limited to the use of cell lines. Further the art of the specification does not specifically provide what is required of a high radiation sensitivity score.
Further the specification provides a supervised learning model using data generated from 48 human cancer cell lines. Thus a supervised learning model using data from 1 sample and 1 control is not predictable of a supervised learning model using 48 cell lines.
The state of prior art and the predictability or unpredictability of the art:
MPEP2164.03 teaches, " The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work.”
The specification recites the “gene name or symbol” and the probes. However, searching Hs.441600 in genecards, (https://www.genecards.org/Search/Keyword?queryString=hs.441600, downloaded 6/26/2018) or pubmed (https://www.ncbi.nlm.nih.gov/pubmed/?term=hs.441600, downloaded 6/26/2018)did not provide any indication of the sequence(s) required.
Benner et al (Trends in Genetics (2001) volume 17, pages 414-418) teaches that, “Here, the ‘homology-implies-equivalency’ assumption is restricted to a subset of homologs that diverged in the most-recent common ancestor of the species sharing the homologs. This strategy is useful, of course. But it is likely to be far less general than is widely thought. Two species living in the same space, almost by axiom, cannot have identical strategies for survival. This, in turn, implies that two orthologous proteins might not contribute to fitness in exactly the same way in two species” (see page 414, 3rd column last full paragraph). Benner specifically describes that although the leptin gene homologs have been found in mice and humans, their affect is different (see page 414, 3rd column last paragraph-3rd column page 415). Benner specifically teaches that the leptin gene in mice plays a major role in obesity, but no such effect has been demonstrated in humans due perhaps to the different evolutionary forces. Benner thus teaches that the activity and function of genes in different species is unpredictable.
May et al (Science (1988) volume 241, page 1441) teaches there are millions of known taxonomic species in each kingdom (table 3). May further teaches there are at least 4,500 known mammalian species (table 3).
The art of Cheung et al (Nature Genetics, 2003, volume 33, pages 422-425) teaches that there is natural variation in gene expression among different individuals. The reference teaches an assessment of natural variation of gene expression in lymphoblastoid cells in humans, and analyzes the variation of expression data among individuals and within individuals (replicates) p.422, last paragraph; Fig 1). The data indicates that, for example, expression of ACTG2 in 35 individuals varied by a factor of 17; and that in expression of the 40 genes with the highest variance ratios, the highest and lowest values differed by a factor of 2.4 or greater (Fig 3).
Saito-Hisaminato et al. (DNA research (2002) volume 9, pages 35-45) teaches that gene expression is not predictable across different human tissues.
The level of skill in the art:
The level of skill in the art is deemed to be high
Quantity of experimentation necessary:
The claims recite “AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195”. Further claim 2 references probes that appear to be from the Affymetrix database 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at”. The recitation of gene symbol or probe identifiers constitutes an attempt to incorporate by reference to the gene symbol or probe identifiers the subject matter which is contained within the recited database record. This recitation constitutes an improper incorporation by reference of essential material since it is material that is necessary to describe the claimed invention. Essential material may not be incorporated by reference to non-patent publications (MPEP 608.01)(p).
Therefore, the claims are rejected for failure to comply with the enablement requirement because the specification fails to provide essential subject matter for the practice of the claimed invention. This rejection can be overcome by deleting the specific reference to the gene symbol or probe identifiers from the claim.
Further it would be unpredictable to generate a score by comparing to any control values as it encompasses any control values from any tissue of any species and does not clearly indicate how a score is being generated or what is being compared.
Further it would be unpredictable to use any sample from any subject as there is no evidence that samples from subjects without cancer or samples that are not cancerous for prediction of response to radiation therapy. The teachings of the specification are limited to cancer cell lines, thus it would be unpredictable to extrapolate the findings of cell lines to healthy tissues or subjects without cancer. Further it would be unpredictable to use samples from different tissues as they have different expression patterns, due to the different functions.
Further it would be unpredictable to use any by multivariate regression analysis or principal component analysis using a single sample and single control as these are statistical methods requiring multiple values to determine statistical differences.
Further it would be unpredictable to use any species as the patient as the teachings of the specification are limited to humans. However gene homologs in different species often have different functions due to different evolutionary pressures. Thus it would be unpredictable to extrapolate the findings from one species to another.
Therefore, in light of the breadth of the claims, the lack of guidance in the specification, the high level of unpredictability in the associated technology, the nature of the invention, the negative teachings in the art, and the quantity of unpredictable experimentation necessary to practice the claimed invention, it would require undue experimentation to practice the invention as claimed.
Written Description
Claims 1-2 and 4 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
The attempts to incorporate subject matter into this application by reference to the AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195 are ineffective because the databases these Gene symbols reference are not US Patents or published patent applications. The attempt to incorporate subject matter into this application by reference to AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195. Further claim 2 references probes that appear to be from the Affymetrix database 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at is ineffective because incorporation by reference under rule 1.57 requires that the incorporation be expressly presented in the specification to be effective.
When the claims are analyzed in light of the specification, the invention encompasses an enormous number of nucleotide molecules. The specification on page 40 teaches probe sets and Gene symbols including those recited in claims 1 and 2. The specification teaches, “Microarrays: analyses using microarrays technology has been widely adopted for generating gene expression data on a genomic scale. Gene expression profiles were from obtained from Affymetrix UI33plus chips from a previously published study by S. Eschrich, H. Zhang, H. Zhao, D. Boulware, J.-H. Lee, G. Bloom, and J. F. Torres-Roca, "Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform.," Int. J. Radiat. Oncol. Biol. Phys., vol. 75, no. 2, pp. 497-505, October 2009” (pages 24-25).. Thus the gene symbols and probes appear to be from an Affymetrix database. The specification does not teach the sequence of the AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195, 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at. Thus the specification appears to teach the probes are correlated or related to the gene symbols, but does not teach what sequence of either probe or gene symbol is required. The claims recite patient and the specification does not define patient. Thus the broadest reasonable interpretation of patient is any subject of any species.
Benner et al (Trends in Genetics (2001) volume 17, pages 414-418) teaches that, “Here, the ‘homology-implies-equivalency’ assumption is restricted to a subset of homologs that diverged in the most-recent common ancestor of the species sharing the homologs. This strategy is useful, of course. But it is likely to be far less general than is widely thought. Two species living in the same space, almost by axiom, cannot have identical strategies for survival. This, in turn, implies that two orthologous proteins might not contribute to fitness in exactly the same way in two species” (see page 414, 3rd column last full paragraph). Benner specifically describes that although the leptin gene homologs have been found in mice and humans, their affect is different (see page 414, 3rd column last paragraph-3rd column page 415). Benner specifically teaches that the leptin gene in mice plays a major role in obesity, but no such effect has been demonstrated in humans due perhaps to the different evolutionary forces. Benner thus teaches that the activity and function of genes in different species is unpredictable.
May et al (Science (1988) volume 241, page 1441) teaches there are millions of known taxonomic species in each kingdom (table 3). May further teaches there are at least 4,500 known mammalian species (table 3).
The art of Cheung et al (Nature Genetics, 2003, volume 33, pages 422-425) teaches that there is natural variation in gene expression among different individuals. The reference teaches an assessment of natural variation of gene expression in lymphoblastoid cells in humans, and analyzes the variation of expression data among individuals and within individuals (replicates) p.422, last paragraph; Fig 1). The data indicates that, for example, expression of ACTG2 in 35 individuals varied by a factor of 17; and that in expression of the 40 genes with the highest variance ratios, the highest and lowest values differed by a factor of 2.4 or greater (Fig 3).
Saito-Hisaminato et al. (DNA research (2002) volume 9, pages 35-45) teaches that gene expression is not predictable across different human tissues.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been disclosed. The instant specification teaches provides no sequences for the recited genes or probes.
Next, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (e.g. other nucleotide sequences or positions with in a specific gene or nucleic acid), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case the specification provides no structural limitations for the recited gene symbol or probes. The claims read in light of the specification encompass any nucleic acid molecule that can broadly be described as the recited gene symbols or probes. This is an enormous genus as searching Hs.441600 in genecards, (https://www.genecards.org/Search/Keyword?queryString=hs.441600, downloaded 6/26/2018) or pubmed (https://www.ncbi.nlm.nih.gov/pubmed/?term=hs.441600, downloaded 6/26/2018) did not provide any indication of the sequence(s) required. Further hs.441600 teaches (http://useast.ensembl.org/Multi/Search/Results?q=hs.441600;site=ensembl, downloaded 1/16/2019) teaches there are numerous sequences in different species with multiple genome locations that are encompassed by this recitation.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed nucleic acids regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993), and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The current situation is a definition of the compound solely based on its functional utility, as a gene symbol or probe set , without any definition of the particular polymorphisms claimed.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
An adequate written description of a DNA, such as the cDNA of the recombinant plasmids and microorganisms of the '525 patent, "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
In the instant application, the provided information regarding nucleic acid “any” AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195, 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at therewith does not constitute an adequate written description of the broad subject matter of the claims, and so one of skill in the art cannot envision the detailed chemical structure of the nucleic acids encompassed by the claimed gene or polymorphisms. Adequate written description requires more than a statement that nucleic acids with a particular quality are part of the invention and reference to a potential method for their identification. The nucleic acid sequence is required.
In conclusion, the limited information provided regarding AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195, 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at is not deemed sufficient to reasonably convey to one skilled in the art nucleic acid molecules claimed.
Thus, having considered the breadth of the claims and the provisions of the specification, it is concluded that the specification does not provide adequate written description for the claims. Further the claim does not provide adequate written description of the comparing step.
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 1-2, 4 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 pre-AIA the applicant regards as the invention.
Claim 1 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method of predicting radiation sensitivity in a subject, however the last positive active step is drawn to treating the subject with radiation therapy when the patient has a high radiation sensitivity score and treating the subject without radiation therapy when the patient has a low radiation sensitivity score. Therefore it is unclear as to whether the method is drawn to predicting radiation sensitivity in a subject or treating the subject with radiation therapy when the patient has a high radiation sensitivity score and treating the subject without radiation therapy when the patient has a low radiation sensitivity score. Further the claim is vague and unclear how the comparison provides a radiation sensitivity score as the specification provides no guidance.
Claim 1 recites, “AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195.” The specification does not provide any indication of what is required of AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195. Searching Hs.441600 in genecards, (https://www.genecards.org/Search/Keyword?queryString=hs.441600, downloaded 6/26/2018) or pubmed (https://www.ncbi.nlm.nih.gov/pubmed/?term=hs.441600, downloaded 6/26/2018)did not provide any indication of the sequence(s) required. Further hs.441600 teaches (http://useast.ensembl.org/Multi/Search/Results?q=hs.441600;site=ensembl, downloaded 1/16/2019) teaches there are numerous sequences in different species with multiple genome locations that are encompassed by this recitation. Thus the metes and bounds of the claim are unclear.
Claim 1 recites, “high radiation sensitivity score” and “low radiation sensitivity score.” The recitation of high and low are relative terms. The specification does not any standard to differentiate a high radiation sensitivity score from a low sensitivity score. Thus the artisan is not adequately apprised of the breadth of the claims.
Claim 1 recites, “f AW979276 (MAGP)(SEQ ID NO: 1), Chromosome 5 Open Reading Frame 56 (C5orf56) (SEQ ID NO: 4)), Cystic fibrosis transmembrane conductance regulator (CFTR), Cytoplasmic FMR1 Interacting Protein 1 (CYFIPI), Hs.441600 (AW592246) (SEQ ID NO: 2), Hs.664912 (BF515306) (SEQ ID NO: 5), Hs.668213 (BG150083)(SEQ ID NO: 6), Interleukin-18 binding protein (IL18BP), Lysine-specific demethylase 5A (KDM5A), LOC100129195 (ZSCAN16-AS1)(SEQ ID NO: 3), and Ras related in brain (RAB) 13 (RAB13).” The metes and bounds are unclear if the information in parenthesis is a limitation, preferred embodiment, or something else.
Claims 2 and 4 are rejected as they depend from claim 1.
Claim 2 recites, “238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at.” The specification provides no indication of what is required of 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at. Thus it is unclear what is required of this.
Claim 4 requires, “wherein the gene expression levels are analyzed by multivariate regression analysis or principal component analysis to calculate the risk score.” It is unclear how the data from a single sample and control values allows for multivariate regression analysis or principal component analysis which require numerous data points from multiple samples.
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 1-2, 4 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation and mental step without significantly more when there is a low radiation therapy score. The claim(s) recite(s) the abstract idea or mental step of comparing. This judicial exception is not integrated into a practical application because when there is a low radiation therapy score no specific treatment is required. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because when there is a low radiation therapy score no specific treatment is required.
Claim analysis
The instant claim 1 is directed towards a method for predicting radiation sensitivity in a subject, comprising:a) assaying a biological sample from the subject for gene expression levels of a gene panel comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, or more genes selected from the group consisting of AW979276 (MAGP)(SEQ ID NO: 1), Chromosome 5 Open Reading Frame 56 (C5orf56) (SEQ ID NO: 4)), Cystic fibrosis transmembrane conductance regulator (CFTR), Cytoplasmic FMR1 Interacting Protein 1 (CYFIPI), Hs.441600 (AW592246) (SEQ ID NO: 2), Hs.664912 (BF515306) (SEQ ID NO: 5), Hs.668213 (BG150083)(SEQ ID NO: 6), Interleukin-18 binding protein (IL18BP), Lysine-specific demethylase 5A (KDM5A), LOC100129195 (ZSCAN16-AS1)(SEQ ID NO: 3), and Ras related in brain (RAB) 13 (RAB13); b) comparing the gene expression levels to control values to generate a radiation sensitivity score; and c) treating the subject with radiation therapy when the patient has a high radiation sensitivity score and treating the subject without radiation therapy when the patient has a low radiation sensitivity score.. The correlation in the preamble in a natural correlation or phenomena. The comparing step is a mental step or abstract idea.
The assaying of a biological sample is considered to be an active step requiring the analysis of a sample.
Dependent claims set forth further limitations to about the assaying probes and methods of generating a score.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea and law of nature or natural phenomena.
With regards to claim 1, the claim recites, “b) comparing the gene expression levels to control values to generate a radiation sensitivity score.” This is an abstract idea or mental step. (UNIVERSITY OF UTAH RESEARCH v. AMBRY GENETICS CORPORATION).
Further the claim in the preamble recites, “method for predicting radiation sensitivity in a subject,” which is a natural correlation.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no if there is a low radiation sensitivity score as there is no specific treatment.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, as the claim requires no specific steps or reagents which require significantly more..
With regards to claim 1 the claim requires a single active step of assaying gene expression in a biological sample. The specification teaches:
“Microarrays: analyses using microarrays technology has been widely adopted for generating gene expression data on a genomic scale. Gene expression profiles were from obtained from Affymetrix UI33plus chips from a previously published study by S. Eschrich, H. Zhang, H. Zhao, D. Boulware, J.-H. Lee, G. Bloom, and J. F. Torres-Roca, "Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform.," Int. J. Radiat. Oncol. Biol. Phys., vol. 75, no. 2, pp. 497-505, October 2009” (pages 24-25).. Thus the gene symbols and probes appear to be from an Affymetrix database. The specification does not teach the sequence of the AW979276, Hs.441600, Hs.664912, Hs.668213, L0C100129195, 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at. Thus the claim does not provide additional steps which are significantly more.
Dependent claims are routine and conventional based on Torres-Roca (US20120053911) and Seita (Plos One (2012) volume 7, e40321) [ages 1-11)
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 4 are is/are rejected under 35 U.S.C. 102(a)(1)/102 (a)(2) as being anticipated by Rico (US2017/0283873).
This rejection is set forth in view of the SEQ ID NO being in the claims and thus not getting priority to prior applications which do not appear to have sequence listings.
With regards to claim 1, Rico claims, “ A method for predicting radiation sensitivity in a subject, comprising: a) assaying a biological sample from the subject for gene expression levels of a gene panel comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, or more genes selected from the group consisting of AW979276, C5orf56, CFTR, CYFIP1, Hs.441600, Hs.664912, Hs.668213, IL18BP, KDM5A, LOC100129195, and RAB13; and b) comparing the gene expression levels to control values to generate a radiation sensitivity score.” (claim 1) Rico claims, “ wherein the gene expression levels are analyzed by multivariate regression analysis or principal component analysis to calculate the risk score.” (claim 4) Rico claims, “The method of claim 1, further comprising treating the subject with radiation therapy if the patient has a high radiation sensitivity score.” (claim 5). Rico claims,” The method of claim 1, further comprising treating the subject without radiation therapy if the patient has a low radiation sensitivity score.” Thus Rico anticipates claim 1 as it claims all the active steps of claim 1.
With regards to claim 2, Rico claims, “wherein the biological sample is assayed using a microarray comprising two or more oligonucleotide probe sets selected from the group consisting of 238735_at, 1564276_at, 215703_at, 208923_at, 244039_x_at, 243559_at, 236687_at, 222868_s_at, 226367_at, 1557062_at, and 202252_at.” Thus Rico claim anticipates claim 2.
With regards to claim 4, Rico claims, “ wherein the gene expression levels are analyzed by multivariate regression analysis or principal component analysis to calculate the risk score.” (claim 4) Thus Rico claim anticipates claim 4.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C.