MYR 1046
`Myriad Genetics, Inc. et al. (Petitioners) v. The Johns Hopkins University (Patent Owner)
`IPR For USPN 7,824,889
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`IN THE CLAIMS
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`Please amendthe following claims as indicated by the status identifier. Patent claims
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`under reexamination but not amendedare indicated as “original.” Patent claims not subject to
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`reexamination are not shown.
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`1. (Amended) A method for determiningan allelic imbalance in a biological sample,
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`comprising the stepsof:
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`distributing isolated nucleic acid template molecules to form a set comprising a plurality
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`of assay samples, wherein the nucleic acid template molecules are isolated from the biological
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`sample:
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`amplifying the isolated nucleic acid template molecules within [a] the set [comprising a
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`plurality of assay samples] to form a population of amplified moleculesin [each of the] individual
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`assay samplesof the set[, wherein the template molecules are obtained from the biological
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`sample];
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`analyzing the amplified molecules in the assay samples of the set to determinea first
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`numberof assay samples which containafirst allelic form of a marker and a second numberof
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`assay samples which contain a secondallelic form of the marker, wherein between 0.1 and 0.9 of
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`the assay samples yield an amplification product of at least one of the first and secondallelic
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`forms of the marker;
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`comparing the first number to the second numberto ascertain an allelic imbalance in the
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`biological sample; and
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`identifying an allelic imbalancein the biological sample.
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`2. (Original) The method of claim 1 wherein the step of amplifying employsreal-time
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`polymerase chain reactions.
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`3. (Original) The method of claim 2 wherein the real-time polymerase chain reactions
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`comprise a dual-labeled fluorogenic probe.
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`4. (Amended) The method of claim 1 further comprising the step of isolating template
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`nucleic acid molecules from the biological sample prior to the step of distributing [wherein
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`between 0.1 and 0.9 of the assay samples yield an amplification product as determined by
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`amplification of the first allelic form of the marker].
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`5. (Amended) The method of claim 1 wherein the step of distributing the isolated nucleic
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`acid template molecules is performed by diluting [wherein between 0.1 and 0.9 of the assay
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`samples yield an amplification product as determined by amplification of the secondallelic form
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`of the marker].
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`6. (Original) The method of claim 1 wherein the amplified molecules in each of the assay
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`samples within the first and second numbers of assay samples are homogeneoussuchthat the first
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`numberof assay samples do not contain the secondallelic form of the marker and the second
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`numberof assay samples do not containthefirst allelic form of the marker.
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`7. (Original) The method of claim 1 wherein the sample is from blood.
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`8. (Amended) A method for determining an allelic imbalance in a biological sample,
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`comprising the stepsof:
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`distributing cell-free nucleic acid template molecules from a biological sample to form a
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`set comprising a plurality of assay samples;
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`amplifying the template molecules within the assay samples to form a population of
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`amplified molecules in the assay samplesof the set;
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`analyzing the amplified molecules in the assay samples of the set to determine a first
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`numberof assay samples which contain a first allelic form of a marker and a second numberof
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`assay samples which contain a secondallelic form of the marker;
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`comparing the first number of assay samples to the second numberof assay samplesto
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`ascertain an allelic imbalance betweenthefirst allelic form and the secondallelic form in the
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`biological sample.
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`9. (Original) The method of claim 8 wherein the sample is from blood.
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`10. (Amended) The method of claim 1 or 8 wherein between 0.1 and 0.6 of the assay
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`samples yield an amplification product_ofat least one of the first and secondallelic forms of the
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`marker.
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`11. (Amended) The method of claim 1 or 8 wherein between 0.3 and 0.5 of the assay
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`samples yield an amplification product of at least one ofthe first and second allelic forms of the
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`marker.
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`12. (Original) The methodof claim 1 or 8 wherein the set comprisesat least 500 assay
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`samples.
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`13. (Original) The method of claim 1 or 8 wherein the set comprisesat least 1000 assay
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`samples.
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`14. (Original) The method of claim 8 wherein the step of amplifying employsreal-time
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`polymerase chain reactions.
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`15. (Original) The method of claim 14 wherein the real-time polymerase chain reactions
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`comprise a dual-labeled fluorogenic probe.
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`16. (Amended) The method of claim 8 wherein the step of distributing is performed by
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`diluting [between 0.1 and 0.9 of the assay samples yield an amplification product as determined
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`by amplificationofthe first allelic form of the marker] .
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`17. (Amended) The method of claim 8 further comprising the step of isolating cell-free
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`nucleic acid template molecules from the biological sample _priorto the step ofdistributing
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`[wherein between 0.1 and 0.9 of the assay samples yield an amplification product as determined
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`by amplification of the secondallelic form of the marker].
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`18. (Original) The methodof claim 8 wherein the amplified molecules in each of the
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`assay samples within the first and second numbers of assay samples are homogeneoussuch that
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`the first number of assay samples do not contain the secondallelic form of the marker and the
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`second numberof assay samples do not contain thefirst allelic form of the marker.
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`Remarks
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`Status of all claims
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`Claims 1-18 are subject to re-examination. Claims 1, 4, 5, 8, 10, 11, 16, and 17 are
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`amended.
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`Support for amendments
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`Claim 1 is amendedto recite a step of distributing isolated nucleic acid template
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`molecules. This is supported at col. 4, lines 37-41, and col. 7, lines 10-12.
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`Claim | is amendedto recite that individual assay samples are formed with amplified
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`molecules rather than each assay sample. Thisis a clarifying amendment to makeit consistent with
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`the recitation later in the claims of between 0.1 and 0.9 of the assay samples yielding an
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`amplification product. See col. 6, lines 15-20.
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`Claim 1 is amendedto recite that the amplification products in 0.1 to 0.9 of the assay
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`samples are of at least one ofthe first and secondallelic forms of the marker. Again this is an
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`attempt to clarify the intended meaning ofthe original recitation. Claims 10 and 11 are similarly
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`amendedfor clarification purposes. See col. 6, lines 3-20.
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`Claims 4 and 17 recite a step of isolating nucleic acid template molecules from the
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`biological sample. This is supportedat col. 7, lines 10-12.
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`Claim 5 and 16 are amendedto recite that the distribution of nucleic acid template
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`molecules is by dilution. This is supported at col. 4, lines 20-41.
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`Claim 8 is amendedto recite cell-free nucleic acid template. This is supported at col. 7,
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`lines 10-14, col. 8, lines 6-7, col. 9, lines 16-18, col. 9, lines 59-61, col. 11, line 29, and col. 12, lines
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`24-25.
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`The claims amendments do not expand the scope of the claims
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`Noneof the amendments enlarge the scope of the patent claims. The amendments add
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`limitations such that no claim as amendedis broader in scope thanall of the patented claims.
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`1.
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`Novelty
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`Claims 1, 4, 5, 7-11, 16 and 17 stand rejected under §102(b) as allegedly anticipated by
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`Bischoff (Human Molec. Genet. 4:395-399, 1995). As described by the Patent and Trademark
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`Office, Bischoff determinesan allelic imbalance in Figure 1, Table 1. The Patent and Trademark
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`Office concedes that Figure 1 and Table | do not anticipate the claims. Final Office Action at page
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`12, lines 1-4.
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`The next experiment Bischoff describes was aimed at determining whethertheallelic
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`imbalance occurredin all cells or only in a subset of the cells. As Bischoff clearly states, “we have
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`used this single cell approach to demonstrate somatic mosaicism in a patient with BWS”(Beckwith
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`Wiedemann Syndrome). Page 397, col. 2, lines 6-10. Bischoff identifies normal biparental
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`inheritance when both alleles are present in a cell and identifies partial paternal isodisomy when only
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`oneallele was present in a single sample. This teaching of Bischofffails to anticipate the invention
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`of independent claims | and 8, as amendedforat least the following reasons.
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`Bischoff does not teach a step of distributing isolated nucleic acid template molecules, as
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`recited in amended claim 1. Bischoff does not teach a step of distributing cell-free nucleic acid
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`template molecules as recited in claim 8 as amended. Bischoff teaches distributing single
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`lymphocytic cells to separate compartments. Oneof ordinary skill in the art would not recognize
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`single cell micromanipulation as fulfilling a step of distribution of either cell-free or isolated nucleic
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`acid template molecules to form a set comprising a plurality of assay samples.
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`Bischoffalso fails to teach the recitation in claim | of “between 0.1 and 0.9 of the assay
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`samples yield an amplification product of at least one of the first and secondallelic formsof the
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`marker.” In Bischoff, Table 2, all single-cell samples yielded an amplification product. “AII”is
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`equivalent to the ratio 1, 1:1, or 100%, which is outside of the recited range recited in amended claim
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`1.
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`Dependent claims 4, 5, 7, 9-11, 16 and 17, dependent on either claim | or claim 8, are not
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`anticipated for at least the same reasons. Therefore all the claims are novel over Bischoff.
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`Please withdraw this rejection.
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`2.
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`Nonobviousness
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`a.
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`Bischoff (Human Molec. Genet. 4:395-399, 1995)
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`Claims 12 and 13 stand rejected under §103(a) as allegedly obvious over Bischoff alone.
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`Claims 12 and 13, dependent on claims 1 or 8, further recite sets of at least 500 and at least 1000
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`assay samples, respectively. The Patent and Trademark Office acknowledges that Bischoff did not
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`teach this element, because Bischoff taught only a set of six. Nonetheless, the Patent and Trademark
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`Office asserts this massive enlargement of the set would have been obviousto one of ordinary skill in
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`the art to provide greater statistical accuracy.
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`To establish a proper prima facie case of obviousness, the following criteria must be
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`established:
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`(1) the prior art reference, or references when combined, mustdisclose or suggest all the
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`claim limitations (See In re Vaeck, 947 F.2d 488 (Fed. Cir. 1991)); (2) the Patent Office must provide
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`an apparent reason to combine the known elements in the claims (See KSR International Co.v.
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`Teleflex Inc., 550 U.S. 398 (2007)); and (3) there must be a reasonable expectation of success in
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`combining the teachings of the reference(s) (See id.). Here, the Patent and Trademark Office fails to
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`establish a primafacie case of obviousness becausethe cited reference does not disclose or suggest
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`each of the claim limitations.
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`The reasons discussed above with respect to lack of anticipation of claim | by Bischoff,
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`apply to the rejection of these claims as well. Thus the prior art reference fails to disclose all the
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`claim limitations, even before considering the additional recitations of claims 12 and 13.
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`Therationale asserted in the rejection for modifying the teaching of Bischoff (greater
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`statistical accuracy) bears no connection to Bischoff’s teaching. Bischoff wastrying to ascertain
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`whether a duplication or mosaicism had occurred. Bischoff got her answerassaying only six cells
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`(six assay samples). One ofordinary skill in the art would not have been motivated to assay more
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`individual cells in more assay samples becausestatistical accuracy wasirrelevant to Bischoff’s
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`determination of genetic mechanism. Bischoff’s analysis was qualitative, not quantitative, and could
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`be determined quite accurately with six cells. Increasing the numberor cells would not have
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`increased the accuracy of the determination.
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`Additionally, other alleged motivations providedin the rejection do not apply to Beckwith-
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`Wiedemanndisease as studied by Bischoff, but rather relate to other uses that appear to be derived
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`from the subject patent. For example, there would have been no motivation for one of skill in the art
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`to apply Bischoff’s method to study tumor margins or monitor reactions to anti-tumortreatments
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`without impermissible hindsight analysis.
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`Forall these reasons, Bischoff does not render claims 12 and 13 obvious. Please withdraw
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`this rejection.
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`b.
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`Bischoff in view of Woudenberg (U.S. 5,928,907)
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`Claims 2, 3, 14, and 15 stand rejected under §103(a) as allegedly obvious over Bischoff
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`and further in view of Woudenberg.
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`Claims 2 and 3 are dependent on claim 1. Claims 14 and 15 depend from claim 8. Claims
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`2, 3, 14 and 15 recite using RT-PCR (real time PCR) to amplify, and claims 3 and 15 further recite
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`dual-labeled, fluorogenic probes.
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`The Office Action fails to establish a prima facie case of obviousness because the cited
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`references fail to disclose or suggest each of the claim limitations. The deficiencies of Bischoff as an
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`anticipatory reference are discussed above. Woudenberg does not remedy these deficiencies.
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`Woudenberg has no relevant
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`teaching regarding distributing isolated or cell-free nucleic acid
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`template molecules to form a set comprising a plurality of assay samples.
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`Claims 2, 3, 14, and 15 are therefore not obvious over Bischoff in view of Woudenberg.
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`Please withdraw this rejection.
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`c.
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`Bischoff in view of Jeffreys (Nuc. Acids Res. 16: 10953-10971, 1988)
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`Claims 6 and 18 stand rejected under §103(a) as allegedly obvious over Bischoff and
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`further in view of Jeffreys. Claims 6 and 18 are dependent on independentclaims | and 8,
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`respectively. Claims 6 and 18 further recite that the first and second numbersof assay samples are
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`homogeneouslyfirst or second allelic form “such that the first number of assay samples do not
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`contain the secondallelic form of the marker and the second numberof assay samples do not
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`contain the first allelic form of the marker.”
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`The Office Action fails to establish a prima facie case of obviousness becausethe cited
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`references fail to disclose or suggest each of the claim limitations and there is no apparent reason to
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`combine the elements from the cited references. Forall of the reasons that independent claims | and
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`8 are not anticipated by Bischoff, dependent claims 6 and 18 are also not obvious over Bischoff and
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`Jeffreys. In addition, as the Office Action concedes, Bischofffails to disclose the limitation that the
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`amplified DNA sequences in the assay samples are homogeneous. However, the Office Action
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`asserts that Jeffreys teaches this aspect.
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`Jeffreys fails to remedy the deficiencies of Bischoff because Jeffreys, like Bischoff,
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`lacks a relevant disclosure or suggestion regarding the analysis of the numberof assay samples
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`in the set which contain a first allelic form of a marker and the number of samples which contain
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`a secondallelic form of the marker, or the formation of homogenousassay samples containing
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`either the first allelic form or the secondallelic form of the marker as recited in the claims.
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`Moreover, it would not have been obviousto one of ordinary skill in the art to combine
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`Jeffreys with Bischoff to meet the limitation of the claims. The combination has been made
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`improperly using hindsight knowledge obtained from the present invention. It is impermissible to
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`use the claimed invention as an instruction manualor “template” to piece together the prior art so that
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`the claimed invention is rendered obvious. Jn re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992).
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`Indeed, this proposed combination would have destroyed the intended purpose of Bischoff.
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`Bischoff already knew whatthe ratio of alleles was in her patient’s blood cell population.
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`At page 395, col. 2, last paragraph, Bischoff describes extracting genomic DNA from the patient’s
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`blood sample. By visual inspection on a polyacrylamide gel electrophoresis, Bischoff determined
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`that four markers had a greater amount of paternalallele. Fig. 1. But that is not the experiment that
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`the Patent and Trademark Office proposes to modify. The Patent and Trademark Office proposes
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`that the molecular analysis of single cells be modified to incorporate the analysis of diluted, bulk
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`DNA. This second experiment of Bischoff was designed to distinguish between two genetic
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`possibilities: either a duplication of a paternal 11p region had occurredin all cells, or two cell lines
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`had different constituents (normal biparental inheritance and partial paternal isodisomy). Shendure
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`declaration under rule 132, at 412. Both genetic models would have yielded the sameratio if
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`analyzed in bulk. Shendure declaration underrule 132, at 412. See also Fig. 1 of Bischoff. That is
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`whyit wascritical that Bischoff perform a single cell analysis. Bischoff needed to keep the two
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`chromosome |1 homologs together to distinguish between the two genetic models. Shendure
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`declaration at (12. Thus, the proposed modification of Bischoff by the technique of Jeffreys would
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`have rendered Bischoff’s method unsuitable for its intended purpose.
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`If a proposed modification would renderthe prior art invention being modified
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`unsatisfactory for its intended purpose, then there is no suggestion or motivation to make the
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`proposed modification. Jn re Gordon, 733 F.2d 900(Fed. Cir. 1984). See also MPEP § 2143.01(V).
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`Additionally, the Patent and Trademark Office did not explain how the proposed
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`modification of Bischoff’s experiment using a diploid amount of DNA (6 pg) would haveresulted in
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`a set of assay samples with sufficient assay samples comprising homogeneousfirst and secondallelic
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`formsas recited in claims 6 and 18.
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`Please withdraw this rejection as the combination of references is improper and would not
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`have yielded the claimed invention.
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`Conclusion
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`Forat least the reasons stated above, and for the reasons stated in the prior response and
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`declaration underrule 132, all claims in this reexamination are patentable and should be confirmed.
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`Therefore, we request that the Patent and Trademark Office issue a certificate of reexamination
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`confirming the patentability of all claims. The absence of additional comments regarding the Office
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`Action does not indicate agreement with or concession of any characterization or requirement. If the
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`Examinerbelieves a telephone conference would expedite prosecution of this application, please
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`telephone the undersigned at 202 824 3000.
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`Wethank the examiners for agreeing to conduct an interview in this case on July 10, 2014.
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`No fees are believed to be due with respect to the filing of this response. However, should
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`any such fees be due, the Commissioneris hereby authorized to charge any such fees in connection
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`with this paper to Deposit Account No. 19-0733.
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`Respectfully submitted,
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`By:
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`/Sarah A Kagan/
`Sarah A. Kagan
`Registration No. 32,141
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`Dated: July 9, 2014
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`Banner & Witcoff, Ltd.
`Customer No. 11332
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