FINAL ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Amendment filed 24 November 2025. Claims 95, 159, and 206-209 remain withdrawn, while claims 79, 96, 100, 103, 107, 110, 141-142, 149, 160, and 210 remain under consideration. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive for the reasons that are set forth below. Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
Applicant’s election without traverse of the species of (a)(i) (mixtures that include both first and second mixtures of nucleic acids as was originally set forth in [now canceled] dependent claim 94, now recited in independent claim 79), with the subspecies of the second mixture encoding “substantially all of a human genome” (originally recited in claim 95 at a), now recited in amended claim 79), and of (b) liposomes comprising phospholipids (as set forth in a) of claim 149), in the reply filed on March 7, 2024 is again acknowledged.
Claims 159 and 206-208 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 7, 2024. Additionally, claims 95 and 209, and the alternative (b) of claim 96, remain withdrawn, for the reasons noted in the Office action mailed January 24, 2025 (see paragraph 9).
Claim Rejections - 35 USC § 103
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 79, 96, 100, 103, 107, 110, 141-142, 149 , 160, and 210 remain rejected under 35 U.S.C. 103 as being unpatentable over Abdueva (US 2014/0371078A1 [18 December 2014; filed 17 June 2014]; cited in IDS) in view of Berg et al (Journal of Microbiological Methods 55:303-309 [2003]; cited in IDS), Lazaro-Ibanez et al (The Prostate 74:1379 [Aug 2014]; previously cited), and Tembe et al (BMC Genomics 15:824 [Sept. 2014]; previously cited), for the reasons given below (which are repeated from the prior Office action).
Abdueva discloses methods for evaluation of copy number variations in samples, including copy number variations (such as duplications/deletions/amplifications) associated with cancer, which variations may be present in samples from individuals having (or suspecting of having) cancer (see entire reference, particularly paragraphs 2, 48, 186, and 232). For use in their methods, Abdueva also discloses several preferred types of marker nucleic acids (“Marker Nucleic Acids for Tracking and Verifying Sample Integrity”) and positive control compositions, including among them controls “for particular cancer-related loci” (see paragraphs 247-267, particularly paragraph 262). Abdueva also more specifically teach preparing controls that incorporate known amplifications in cases when cancers are known to be “associated with particular amplifications (e.g., breast cancer associated with 20Q13)” (paragraph 267). Abdueva also teach that various methods may be used to facilitate incorporation of markers/controls into samples to be, or in the process of being, tested, with one such preferred method being the use of “cell-delivery carriers including pH-sensitive and cationic liposomes” to allow for delivery of markers into cells of a sample being tested (see paragraph 251). While Abdueva do not employ the terms “genotype” and “neoplasm” in describing their methods and markers/controls, it is an inherent property of the cancer-associated controls disclosed by Abdueva that they correspond to a plurality of genotypes “associated with a neoplasm” (particularly given the breadth of this claim language); it is also noted that Abdueva disclose controls for cancer related “loci” (i.e., not a single locus). With regard to mixtures of first and second nucleic acids wherein the second nucleic acids include “alternative” genotypes to those of “first” nucleic acids, Abdueva teach the use of mixed sequences and mixed genomes as controls, including controls prepared using genomic DNA from cells of two different subjects, one having an aneuploidy of interest (see, e.g., paragraphs 250 and 264-265); such controls constitute admixtures of alternative genotypes. While aneuploidies (such as trisomies) are clearly preferred embodiments of Abdueva’s invention, Abdueva also explicitly teach that their descriptions related to such preferred embodiments also apply to “other partial aneuploidies including for example, various segment amplification and/or deletions” such as those associated with “various cancers” (paragraph 267). Abdueva also teach that a preferred sample for analysis via their methods includes “a plasma sample from a cancer patient” (paragraph 186), providing further motivation to prepare controls/markers for use in cancer diagnostics. Given these teachings of Abdueva, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have adopted Abdueva’s suggestions regarding the use of both cancer marker nucleic acids and/or genomic DNA of multiple subjects as a convenient source of control nucleic acids, resulting in nucleic acid mixtures meeting the majority of the requirements of the claims.
Abdueva thus teaches controls meeting all requirements of claim 79, other than:
a) explicitly teaching that their nucleic acid compositions/mixtures be “incorporated into the liposomes” (as Abdueva state that marker nucleic acids are to be “combined with” a liposome carrier, which is not clearly equivalent to “incorporation into” the liposomes), with the liposomes meeting the requirement of having an average diameter of “about 30 nm to about 300 nm”; and
b) explicitly teaching a control including “at least three nucleotide sequences” encoding “at least three genotypes” that are associated with “at least three types of neoplasms”, as well as alternates of each of those genotypes.
Berg et al teach the use of liposomes containing target nucleic acids as “cell-mimicking vehicles” for use as internal controls in amplification-based DNA detection assays, noting that such controls may be introduced “directly into the crude biological specimens”, and that they were found to be versatile and “applicable for whole process quality control” (see entire reference, particularly the Abstract). Berg et al teach incorporating control nucleic acids into liposomes via a freeze/thawing procedure, with the liposomes being loaded with “relatively few DNA molecules” and adjusted in size so as to prepare “synthetic cell-mimicking particles” (see page 304, right column-page 305, left column). Berg et al state that their liposome controls were tested for their ability to serve “as a tool for whole process quality assurance of nucleic acid amplification-based analysis” (page 307, right column), noting that the “use of naked internal control gives only a partial quality assurance of the nucleic acid –based amplification assays” (page308, left column), while “the nonviable cell-mimicking liposome/internal control particles seem to be versatile and applicable for whole process quality control of nucleic acid amplification-based assays for detection of various pathogens and cells” (page 309, left column).
Lazaro-Ibanez et al disclose analyzing the genomic DNA (gDNA) content of extracellular vesicles - including apoptotic bodies, microvesicles, and exosomes - from both prostate cancer (PCa) cell lines and plasma from PCa patients (as well as healthy controls); see entire reference, particularly the Abstract. Among the vesicles disclosed by Lazaro-Ibanez et al are LNCaP-derived vesicles including multiple genotypes known to be “associated with a neoplasm”, specifically a PTEN mutation in codon 6, and a TP53 mutation in codon 215 (see page 1385, right column-page 1387, left column, and in particular Figure 4, panel C). Lazaro-Ibanez et al also disclose testing for an MLH1 mutation known to be associated with prostate cancer (page 1386-1387, left column), and disclose the use of three different cell lines derived from three different prostate cancer neoplasms (see, e.g., page 1380, right column), such that Lazaro-Ibanez et al teach and suggest a benefit for analyzing three different genotypes known to associated with different neoplasms. Lazaro-Ibanez et al also teach the sizes of different extracellular vesicles tested, including apoptotic bodies (taught as being 1-4 um in size), microvesicles (MVs) (taught as being 0.2-1.0 um in size), and exosomes (EXOs)(taught as being 40-100 nm in size) (see page 1380, left column, first full paragraph).
Tembe et al teach nine synthetic RNA transcripts corresponding to oncogenic fusion genes, which transcripts may be employed as spike-in references/controls, allowing for evaluation of assay performance (see entire reference, particularly page 2/9, page 4/9, and Figure 2). Tembe et al disclose the genes that comprise each fusion, which encompass multiple fusions including genes from different chromosomes, and which fusions are associated with “at least three” different cancers/neoplasms (see, e.g., Figure 1, and Tembe et al’s teaching of the associations of BCR-ABL with chronic myelogenous leukemia, PML-RAR with acute promyelocytic leukemia, and EML4-ALK with non-small cell lung carcinoma (see page 1, both columns)). The different fusions taught by Tembe et al are each nucleotide sequences including sequences from at least two different chromosomes, which nucleotide sequences inherently constitute different genotypes that are associated with different diseases/conditions. In applying their constructs to one type of cancer detection (next generation RNA sequencing), Tembe et al teach that equimolar amounts of their nine different fusions were pooled and titrated into total RNA of a cancer cell line “at ten different abundances” (page 2/9, right column), with the quality and type of results obtained with each of these different dilutions being tested and compared (see, e.g., page 4/9, right column).
In view of the teachings of Abdueva, Berg et al, Lazaro-Ibanez et al, and Tembe et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have prepared (by mixing) nucleic acid compositions including at least three target genotypes and corresponding alternate genotypes “associated with at least 3 different types of neoplasms” - with the alternative genotypes being represented by a complete genome (such as from a healthy control subject) – and to have incorporated those nucleic acids into liposomes meeting the requirements of the claims prior to use, and thereby to have prepared a control as claimed. Given the teachings of Abdueva regarding the application of their methods and controls to cancer detection, and the teachings of Lazaro-Ibanez et al of at least three genotypes associated with different prostate cancer neoplasms that may occur within naturally occurring microvesicles, an ordinary artisan would have been motivated to have prepared such liposomes simply for the benefit of use as controls in detection of such vesicles (and/or simply for use as controls within a liquid sample such as blood, as taught by Abdueva). While it is noted that Abdueva teach a variety of alternative embodiments of their controls, including only some which involve the use of complete genomes, absent the showing of unexpected results, any of these alternatives taught by Abdueva would have been obvious to one of ordinary skill in the art. Furthermore, with regard to the preparation of such constructs representing additional genotypes – including genotypes “associated with at least 3 different types of neoplasms”, as set forth in amended claim 79 - Tembe et al teach the use together of at least three such genotypes, associated with at least three different types of cancers (as discussed above). Thus, Tembe et al establish both the successful use of controls representing the type of genotypes set forth in the claims, and the fact that an ordinary artisan would have been motivated to have prepared such controls to allow for the simultaneous detection of such multiple genotypes associated with different cancers/neoplasms, such that the preparation of such controls would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. An ordinary artisan would have been motivated to have prepared such controls simply for the benefit of facilitating simultaneous testing for a variety of different cancers/neoplasms. Additionally, Tembe et al preparation of controls titrated into total RNA of a cell at various abundances would have further suggested to one of ordinary skill in the art the use of total cellular material, as well as controls including various different abundances.
Regarding the range of 30-300 nm as recited in the claims, while this range is not explicitly taught by Lazaro-Ibanez et al, it overlaps that of multiple naturally occurring extracellular vesicles taught by Lazaro-Ibanez et al (including that of exosomes and smaller microvesicles), such that absent a showing of unexpected results, the size range of the claims is reasonably suggested by the cited art (see MPEP 2144.05, noting that in cases where claimed ranges overlap prior art ranges, a prima facie case of obviousness exists). Additionally, with regard to the selection and successful use of the alternative of liposome controls more generally, an ordinary artisan would have been motivated to have made such a modification for the benefit of preparing a composition that would function successfully in the delivery of the marker/control nucleic acids into a sample intended for testing or in the process of being tested, as taught by Abdueva, and for the further benefit – as taught by Berg et al – of employing a control that mimics the natural target of interest (as compared to a naked nucleic acid control) and which allows for whole process quality control. Further, given Berg et al’s teachings of the successful preparation of such controls via the incorporation of nucleic acids into liposomes, and their disclosure that their liposome controls are suitable for use in amplification-based assays – as well as Lazaro-Ibanez et al and Tembe et al’s teachings of multiple genotypes, and Abdueva’s explicit disclosure of the use of liposome controls in their methods - an ordinary artisan would have had a reasonable expectation of success in preparing and using such controls ‘in identifying a plurality of genotypes” (as recited in the preamble of independent claim 79). Additionally and/or alternatively, given Tembe et al’s teachings of the testing of different concentrations/amounts/ratios of nucleic acids in controls, an ordinary artisan would have been motivated to have prepared any of a variety of different sizes of liposomes and different amounts/ratios of nucleic acids therein, simply to facilitate testing of different types of controls having different properties in different assays/methods – as suggested by Tembe et al – simply in order to optimize procedures for the use of such products. As the claims are drawn to products, and not to any particular method of use of a “control”, or any particular manner of use of the claimed product to achieve “identifying a plurality of genotypes”, the claimed product need not function in any specific way (as what is claimed is the product itself).
With further regard to dependent claims 96, 103, and 210, as well as claim 107, Abdueva disclose and exemplify the collection and use in their methods of peripheral blood (as well as blood/plasma/serum and a “blood fraction”) (see, e.g., paragraphs 12, 64, 96, 99, 231, 233-234, and 241), noting that their teachings of blood, plasma, and serum “expressly encompass fractions or processed portions thereof” (paragraphs 231 and 234). Further, it is reiterated Abdueva also teach that controls may be prepared using genomic DNA from cells of two different subjects, one having the aneuploidy of interest (see paragraph 265); while aneuploidies (such as trisomies) are clearly preferred embodiments of Abdueva’s invention, Abdueva also explicitly teach that their descriptions related to such preferred embodiments also apply to “other partial aneuploidies including for example, various segment amplification and/or deletions” such as those associated with “various cancers” (paragraph 267). Abdueva also teach that a preferred sample for analysis via their methods includes “a plasma sample from a cancer patient” (paragraph 186), providing further motivation to prepare controls/markers for use in the methods taught by Abdueva. Given these teachings of Abdueva, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have adopted Abdueva’s suggestions regarding the use of blood/blood components (such as PMBC genomes) and genomic DNA of multiple subjects as a convenient source of control nucleic acids, resulting in nucleic acid mixtures meeting the requirements of the claims (and thus – given the combined teachings of Abdueva, Berg et al, Lazaro-Ibanez et al, and Tembe et al - resulting in liposomes as claimed). Furthermore, the modifications taught be Abdueva - when practiced with regard to genomic DNA from cells of two different subjects, one being heterozygous for any combination of multiple cancer mutations, would have resulted in a control meeting the requirements of claim 103 - and given Tembe et al’s teachings of the testing/use of numerous different “abundances” of nucleic acid constructs, an ordinary artisan would have been motivated to have prepared a variety of different ratios/dilutions of nucleic acids, suggesting controls meeting the requirements of claims 103, 107, and 210 (again, as the products claimed are not limited to any particular use, and as the preparation of a variety of different possible controls for testing/optimization of assays is suggested by the cited art).
With regard to dependent claim 100, given the scope of Abdueva’s teachings and the disclosure of multiple genotypes of Lazaro-Ibanez et al and Tembe et al (as discussed above), controls including mixtures of nucleic acids comprising multiple sequences encoding genotypes associated with a neoplasm are clearly suggested by the combined teachings of Abdueva, Berg et al, Lazaro-Ibanez et al, and Tembe et al.
Regarding claim 110, Abdueva teach selecting lengths for control nucleic acids that correspond to the length of the corresponding target of detection, and disclose various lengths of fragments that are encompassed by the claims (see, e.g., paragraph 257); thus, the teachings of Abdueva et al in view of Berg et al, Lazaro-Ibanez et al, and Tembe et al suggest what is claimed.
Regarding claims 141-142, Abdueva teaches adding their controls to a test sample, including the preferred test samples of blood, plasma, or serum, which is sufficient to teach and suggest what is claimed; it is noted that human blood is explicitly taught at, e.g., paragraphs 64 and 96.
Regarding claim 149, Berg et al teach that their liposomes comprise phospholipids (see, e.g., page 304, left column, first full paragraph), such that liposomes meeting the requirements of the claim are suggested by Abdueva in view of Berg et al, Lazaro-Ibanez et al, and Tembe et al.
Regarding claim 160, it is noted that the size range of about 100-300 nm also overlaps the size ranges taught by Lazaro-Ibanez et al, and it is thus suggested by the combined teachings of the prior art for the same reasons noted above regarding the broader range recited in independent claim 79.
The Reply of 24 November 2025 traverses the rejection on the following grounds.
a) First, Applicant summarizes requirements of a proper obviousness rejection (particularly with regard to the required “reasonable expectation of success” and the impermissibility of hindsight reconstruction, and urges that the prior art relied upon does not teach or render obvious every element of the claimed invention, and that “one of ordinary skill in the art would have had no reasonable expectation of success in arriving at the claimed invention” (Reply pages 12-13).
In response, it is noted that the examiner does not dispute the fact that a proper rejection under 35 USC 103 cannot employ hindsight reconstruction and requires a reasonable expectation of success; however, the rejection of the claims (which is repeated above) provides an explanation as to why an ordinary artisan would in fact have had a reasonable expectation of success in preparing a product meeting all requirements of the present claims. Further, with regard to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
b) Next, Applicant argues that Abdueva “does not teach or suggest the features of claim 79” (Reply pages 13-16), and particularly that some teachings relied upon in the rejection pertain to a marker nucleic acid rather than an in-process control, as well as to a test sample rather than an in-process control, etc. (page 13 bridging to page 14). While Applicant acknowledges that Abdueva references “cancer-related aneuploidies including deletions and repeats” and also “mentions cancer briefly” in several locations,
The Reply urges that “the passages cited by the Office….relate to general aneuploidies and general ‘cancer-related loci’ or ‘pluralities’, and do not disclose or suggest any specific structural features of a neoplasm control, let alone one comprising a first and second mixture of nucleic acids comprising at least 3 nucleotide sequences encoding 3 genotypes associated with 3 different types of neoplasm” as required by the claims (Reply page 14). Applicant further argues that the controls disclosed by Abdueva “are for fetal aneuploidy assays and would not properly validate diagnostic assays if the fetal DNA is not extracted properly” (citing to teachings in the instant application regarding this issue), whereas a control as disclosed in the application “mimics cfDNA that contains genotypes associated with a neoplasm”, providing improved controls for cfDNA assays that “would improve the quality of diagnostic testing” (Reply page 14 bridging to page 15). The Reply cites to teachings in Abueva regarding the addition of “marker nucleic acids” to biopsy specimens, and acknowledging that Abdueva (at paragraph 251) discloses that marker nucleic acids may be combined with a “carrier that delivers the marker molecules into the cells of the biological sample” (and it is noted by the examiner that paragraph 251 also states that cell-delivery carriers “include pH-sensitive and cationic liposomes”); however, Applicant argues that these teachings of Abdueva pertain to marker nucleic acids “not the positive controls, which are a separate entity from the positive controls of Abdueva”, and urges that Abdueva “does not mention liposome encapsulation of positive controls at all” (Reply page 15). The Reply contrasts this alleged lack of teachings in Abdueva with the disclosure of the instant application, urging that “the present application uses liposome encapsulation to solve the problem of aggregation of nucleic acid controls”, and asserts that because Abdueva “does not disclose any effect of liposome encapsulation on the aggregation of nucleic acid controls, the skilled person could not have had a reasonable expectation of success in solving this problem starting from Abdueva” (Reply page 15 bridging to page 16).
These arguments have been thoroughly considered but are not persuasive.
First, it is noted that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). With respect to the issue of a “marker nucleic acid” as compared to an “in process control”, while the examiner agrees that the reference discloses and discusses both of these, Abdueva’s teachings clearly encompass the use of their disclosed/discussed marker nucleic acids (as well as compositions prepared therefrom, of which one embodiment is liposomes [as discussed in the rejection]) as controls, including in-process controls. For example, following the discussion of various types of marker nucleic acids and marker nucleic acid containing compositions, at paragraphs 247-248, Abdueva at paragraphs 259-267 provides a section describing “Sample Controls (e.g., in Process Positive Controls for Sequencing and/or Analysis)” that begins with the statement (see paragraph 260) “In various embodiments marker sequences introduced into samples, e.g., as described above, can function as positive controls” (going on to provide examples as discussed in the rejection). Further, the teachings of Abueva are sufficient to suggest a variety of different embodiments of marker nucleic acids (also usable as controls), and such markers are taught as being combined with test samples, subjected to a variety of processes (including fractionation, sequencing, etc.; see paragraphs 247-251). It is also reiterated that the claims are directed to a product – a control – not a particular use of the claimed product; the prior art need only suggest the product as claimed. With regard to Applicant’s argument that Abdueva fails to disclose or suggest “specific structural features of a neoplasm control” including mixtures of different sequences and genotypes, etc., again, the rejection is based on a combination of references that suggest what is claimed (not Abdueva alone), and Abdueva clearly do teach and suggest markers/controls for use in cancer testing applications; while this is clearly not Abdueva’s most preferred embodiment, as is discussed in MPEP 2123, a “reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments”, and “examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments”. It is noted that the claims encompass are also not limited to specific structures/sequences, but broadly encompass any “genotypes” have the generally-recited characteristics set forth in the claims. Regarding Applicant’s assertion that controls disclosed by Abdueva “would not properly validate diagnostic assays if” fetal DNA “is not extracted properly”, again, the rejection is based on the teachings of a combination of references, and the claims only require a “control”, not a method in which the claimed product is employed in a particular way. With respect to the issue of Abueva failing to teach an effect of liposome encapsulation on “the aggregation of nucleic acid controls”, it is not necessary for Abdueva (or any of the relied-upon references) to teach the specific advantage in order for the claimed invention to be rendered obvious; the cited art must teach and suggest what is claimed, but the reason or motivation to prepare the claimed product need not be the same motivation taught by Applicant (see MPEP 2144(IV)).
c) Next, Applicant argues that Berg does not remedy the “deficiencies of Abdueva” (Reply pages 16-18). The Reply argues that a “skilled person would not have been motivated to incorporate the compositions of cell free DNA of Abdueva into liposomes taught in Berg to mimic cells, since the analysis in Abdueva is performed on cell free DNA” (referring in particular to Example 4 of Abdueva), and urges that Berg relates to whole process controls involving liposomes intended to mimic C. trachomatis cells, which liposomes differ in composition as compared to those of the claims and which are synthesized to be around 400 nm in diameter (Reply page 16 bridging to page 17). Applicant argues that it would not have been obvious “for a skilled person to incorporate the composition of cell-free DNA in Abdueva into liposomes taught in Berg” and that motivation to do so is lacking, with the ‘intention of using liposomes in Berg” being “entirely different from even the very limited mention of liposomes in Abdueva” (Reply page 17). The Reply also argues that “it is apparent that in practice the control in Berg has the potential to interfere with the assay performance”, and urges that Berg’s teaching of liposomes of 400 nm in diameter constitutes a “teaching away” from liposomes smaller than 400 nm.
These arguments have been thoroughly considered but are not persuasive.
With regard to the issue of Abdueva’s preferred teachings regarding cfDNA, it is reiterated that a “reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments”, and “examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments” (MPEP 2123); the features of the claimed invention that are taught and suggested by Abdueva are as indicated in the rejection of the claims. The rejection does not indicate that the prior art suggests incorporating cfDNA into liposomes having the features taught by Berg; rather, the rejection is based upon the combination of teachings of Abdueva, Berg, Lazaro-Ibanez, and Tembe (again, as set forth above). Further, with regard to the issue of liposomes 400 nm in size, while the rejection did not rely on the teachings of Berg with regard to liposome size, it is noted that the claims do not exclude a control including such larger liposomes; the claim recites that “the average diameter of the liposomes is about 30 nm to about 300 nm”, such that liposomes larger than 300 nm may clearly be present (so long as the “average diameter” of the liposomes of the control are within the recited range). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
d) Applicant next argues that the alleged deficiencies of Abdueva and Berg are not remedied by Lazaro-Ibanez (Reply pages 18-21). In particular, Applicant states that Lazaro-Ibanez fails to teach or suggest a control as claimed (including with regard to the required genotypes and liposome average diameter) and that “a skilled person would have understood from Lazaro-Ibanez that such an arrangement is inoperable and would have been taught away from this development” (Reply page 18). Applicant urges that the genotypes of Lazaro-Ibanez are disclosed as being associated with one type of neoplasm and thus do not meet the requirements of the claims (Reply page 18 to page 19), and that while the claimed controls require that the recited admixture is “encapsulated within liposomes”, the vesicles of Lazaro-Ibanez do not and cannot as they “are formed by the shedding of plasma membrane from individual cells” and thus “can only comprise one human genome, from one cell” (Reply page 19).
The Reply also discusses the different sizes/types of vesicle taught by Lazaro-Ibanez, contrasting them with liposomes having an average diameter of “about 30 nm to about 300 nm” as set forth in the claims (Reply page 19), and argues that the genetic compositions of the different vesicle types as disclosed by Lazaro-Ibanez do not meet the requirements of the claims with regard to “at least 3 nucleotide sequences encoding 3 genotypes associated with 3 different types of neoplasms” (Reply page 20). Applicant also argues that Lazaro-Ibanez teach away from the feasibility of smaller vesicles of the type claimed having the capability of encapsulating the nucleotide sequence admixtures required by the claims (Reply page 21).
These arguments have been thoroughly considered but are not persuasive.
First, it is reiterated that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references; the rejection does not assert that they types of vesicles disclosed by Lazaro-Ibanez et al meet the requirements of the claims, but rather than the combined teachings of Abdueva, Berg, Lazaro-Ibanez, and Tembe suggest what is claimed. Second, it is reiterated that while the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. The present claims (see text of independent claim 79) do not require, e.g., an admixture as specified in the claims that is encapsulated within liposomes of a particular size; rather, the claims recite “the admixture…is incorporated into the liposomes” (i.e., multiple/plural “liposomes”, with no need for such liposomes to be identical/have identical contents), and that “the average diameter of the liposomes is about 30 nm to about 300 nm” (such that the actual population of liposomes may include much larger [as well as much smaller] vesicles, so long as the “average diameter” of the liposomes of the claimed control have an average diameter as specified). Further, as already noted, the combined teachings of the cited art include disclosures of controls representing multiple cancer loci (Abdueva) as well as three different prostate cancer neoplasms (Lazaro-Ibanez) and multiple different fusions including sequences originating from different chromosomes and associated with different cancer types (Tembe), such that the combined teachings of the prior art (which is what the rejection relies upon) are sufficient to suggest what is actually recited in the claims (as discussed in the rejection itself). Finally, with regard to the issue of operability, the claims simply require a “control for use in identifying a plurality of genotypes”; there are no particular method steps required, or other limitations on the manner of use of the product being claimed, that would render what is suggested by the cited art “inoperable” for use as some type of “control”. Thus, while Applicant’s arguments might be effective with respect to a narrower/more specific type of claim, they are not persuasive with regard to the claims actually under consideration.
e) The reply also argues that the “deficiencies of Abdueva, Berg, and Lazaro-Ibanez are not remedied by Tembe” (Reply page 21), summarizing the nature of the control(s) taught by Tembe, and urging that Tembe “provides no disclosure to suggest that the RNA transcripts disclosed therein could be incorporated into liposomes”, and particularly liposomes meeting the size requirements of the claims (Reply page 220).
These arguments have also been thoroughly considered but are not persuasive, as the features allegedly absent from Tembe (liposomes, controls comprising liposomes embraced by the size range set forth in the claims, etc.) are taught by other references relied upon in the rejection (as discussed above).
f) Finally, the Reply urges that the claimed invention provides unexpected benefits/ results, including control stability provided by liposome encapsulation (Reply page 22 bridging to page 23), and the fact that the “claimed control surprisingly allows multiplex detection of neoplasm-associated genotypes”, with the Reply specifically referencing an example involving 9 genotypes and liposomes with an average diameter of 100 nm (Reply page 23 bridging to page 24).
These arguments have been thoroughly considered but are not persuasive. First, with regard to the issue of stability of nucleic acids incorporated into liposomes as compared to those that are not, such a benefit is simply a property/characteristic of the liposomal control composition; thus, preparation of such a control in the manner suggested by the prior art – resulting in a product meeting the requirements of the present claims - also necessarily results in a composition having this feature. Regarding the issue of multiplex detection, the claims are directed to a control, not to any particular use thereof (i.e., multiplexing is not a required feature of what is being claimed). Further, the example cited by Applicant pertains to a nucleic acids controls comprising 9 genotypes and liposomes with an average diameter of 100 nm, which is clearly not commensurate in scope with the product currently being claimed (see MPEP 716.02(d), noting that objective evidence of nonobviousness must be commensurate in scope with the claims).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682