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 .
Claim Status
Claims 1-13 are pending.
Claim Objections
Claims 1-13 are objected to because of the following informalities:
Claims 1 and 6-13 include periods before the end of the claim (e.g. “a.” in claim 1). Periods are only allowed at the end of a claim. Applicant is directed to MPEP 608.01(m) which states “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).”
To overcome this objection, it is recommended that Applicant amend all instances of periods before the end of the claim to parentheses (for example, “a.” in claim 1 would be amended to “a)” or “(a)”).
Claim 1 recites “discharging the tissue-containing a liquid phase depleted of the paraffin.” The “a” between “containing” and “liquid” is grammatically incorrect. It is recommended that Applicant amend to “tissue-containing liquid phase.”
Claim 1, step d recites “separating the molten paraffin by rotating the centrifugal microfluidic biochip about an axis of rotation to produce separated liquid paraffin.” While is it is clear that the paraffin is separated from the formalin-fixed paraffin-embedded tissue (FFPE) from the preamble and step a, it is recommended that Applicant amend to indicate in step d that the separated liquid paraffin is separated from the formalin-fixed paraffin-embedded tissue (FFPE) to improve the clarity and readability of the claims.
Claims 2-12 each recite “a method according to” a previous claim and claim 13 recites “a method for molecular analysis of formalin fixed paraffin-embedded tissue (FFPE), according to claim 1.” While is it clear that each of these claims intend to depend on and refer to the previous claims that they cite, to improve the clarity and readability of the claims, it is recommended that Applicant amend these instance of “a method” to “the method” (e.g. claim 2 “a method according to claim 1” would be amended to “the method according to claim 1”).
Claims 11-12 each are grammatically incorrect because they recite incomplete clauses that do not include a verb. Specifically, the clauses of “the temperature of the first chamber wall through which the temperature input takes place being above the melting temperature of paraffin and the temperature of a second chamber wall opposite the first chamber wall being below the melting temperature of paraffin” (instant claim 11) and “the centrifugal microfluidic biochip being rotated about the axis of rotation at higher frequency than in step d. in order to cool the second chamber wall” (instant claim 12) are incomplete clauses that do not recite a verb.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (b)
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 1-13 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “the tissue-containing a liquid phase depleted of the paraffin from the first chamber” as part of step f. However, while claim 1 recites “the tissue-containing a liquid phase” the claims does not have a prior recitation of “a tissue-containing a liquid phase.” Therefore, there is improper antecedent basis for this phrase, it is unclear how “the tissue-containing a liquid phase” is integrated into the method steps of claim 1, and the metes and bounds of the claim are indefinite.
By nature of their ultimate dependency on claim 1, claims 2-13 are also rejected.
Claim 6 recites “the fluid held in the centrifugal microfluidic biochip.” However, claim 1, upon which claim 6 depends, does not recite “a fluid held in the centrifugal microfluidic biochip.” Therefore, the metes and bounds of the claim is unclear because it is what “the fluid held in the centrifugal microfluidic biochip” is intended to encompass, it is unclear how this limitation is incorporated into the method steps of claim 1, and there is improper antecedent basis for this phrase.
Claim 13 recites “A method for molecular analysis of formalin-fixed paraffin-embedded tissue (FFPE) according to claim 1.” However, claim 1, upon which claim 13 depends, recites “a method for deparaffinizing formalin-fixed paraffin-embedded tissue (FFPE) in a centrifugal microfluidic biochip” and does not recite “A method for molecular analysis of formalin-fixed paraffin-embedded tissue” or any steps of a method for molecular analysis. Therefore, the scope of the claim is indefinite because there is no nexus between the preamble of claim 13 and the preamble and method steps of claim 1, upon which it depends and the metes and bounds of a method “according to claim 1” that is also a method “a method for molecular analysis of formalin-fixed paraffin-embedded tissue” is indefinite.
Claim 13 recites a method step of “analyzing the liquid phase containing the tissue with respect to at least one molecular property in a manner known per se” which includes “in a manner known per se.” This renders the scope of the claim indefinite because the recited limitation of “in a manner known per se” appears to refer to method steps, while the instant specification does not define or provide examples that would lead one of ordinary skill to what the breadth of the specific method steps of “in a manner known per se” encompasses. Therefore, the metes and bounds of the claims are indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 recites “step b. comprises introducing the fluid held in the centrifugal microfluidic biochip into the first chamber.” However, claim 1, upon which claim 6 depends, already recites “introducing a fluid into the first chamber.” Since a fluid has already been introduced into the first chamber, claim 6 cannot further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 6, 8-9, 10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffman (WO-2017202729-A1; see IDS filed 15th, October, 2024; citations refer to attached translation) in view of Shih et al. (US-20210387179-A1; see IDS filed 15th, October, 2024; henceforth “Shih”) as evidenced by Lim et al. (Microsc Res Tech. 2010 Aug;73(8):761-5.; henceforth ”Lim”).
Regarding claim 1, Hoffman discloses a method for paraffin-embedded tissue sample preparation with a microfluidic device (claims 1-12; abstract) having a fluidic system comprising a plurality of chambers, said method comprising:
placing formalin-fixed, paraffin-embedded tissue (FFPE) (“paraffin-embedded tissue sample” and “the tissue may have been treated with formalin prior to embedding in paraffin, and such prepared tissue is also referred to as formalin-fixed paraffin-embedded tissue, FFPE tissue” (pg. 2 5th para.) including paraffin into a first chamber of a fluidic system of a microfluidic biochip (“Introducing a paraffin-embedded tissue sample (1) into a first chamber (110) of the microfluidic device (100)” claims pg. 1),
introducing a fluid (oil) into the first chamber (“Introducing oil into the first chamber” claims pg. 1; pg. 2 3rd-4th, 9th and 13th para.)
melting the paraffin by tempering the first chamber to a temperature above the melting temperature of the paraffin to produce molten paraffin (“the oil being brought to a first temperature by a heater of the microfluidic device” claim 1; see also “due to the first temperature of the oil, the paraffin melts and combines with the oil”; pg. 3 19th para.)
separating the molten paraffin (“loop-shaped channel to an inlet in the first chamber. This allows repeated transport of the oil for extracting the paraffin through the first chamber” pg. 2).
solidifying the separated liquid paraffin by controlling the temperature of at least a sub-region of the first chamber to a temperature below the melting temperature of the paraffin (addition of the lysis buffer leads to a reduction in the temperature; claims pg. 2 10th para.)
discharging the tissue-containing liquid phase depleted of the paraffin from the first chamber (“the two-phase mixture is divided by the filter into a non-polar phase containing the oil and a polar phase containing the aqueous components of the aqueous solution. The two phases can then advantageously be further processed separately” pg. 2 10th para.).
However, regarding claim 1, although Hoffman teaches the microfluidic device can be a microfluidic a lab-on-a-chip device (pg. 2 5th para.), and Hoffman teaches a method step of d. separating the molten paraffin, Hoffman is silent to a centrifugal microfluidic biochip, and Hoffman is silent to performing step d. of separating the molten paraffin by rotating the centrifugal microfluidic biochip about an axis of rotation to produce separated liquid paraffin.
Nevertheless, regarding claim 1, Shih teaches a centrifugal microfluidic biochip having a fluidic system comprising a plurality of chambers (“centrifugal compound collecting platform” abstract), and Shih teaches a method step of using centrifugal force with the device to drive the fluid to flow outward in the radial direction, separating compounds with different characteristics and collecting them in different chambers (“centrifugal compound collecting platform disclosed in the present invention mainly uses a centrifugal force to drive the fluid to flow outward in the radial direction when the motor rotates” and “compounds with different characteristics can be separated and collected in different collecting chambers” abstract and claim 11 step a4 ; see also Figures 2, 14-15, 17; para. [0001, 0006-0011, 0026-0030, 0032, 0034-0039, 0041, 0043, 0047, 0049, 0052, 0054, 0056, 0058, 0060-0063]; claims 1-15). Shih teaches using a centrifugal platform has the benefits of making the experimental platform smaller, allowing automatic inspection instead of manual operation, reducing amounts of reagent, higher manipulability, and reducing time (para. [0004]).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Hoffman, and combine the known prior art elements of the centrifugal microfluidic biochip and the method step of separating by rotating the centrifugal microfluidic biochip about an axis of rotation to produce separated compounds of Shih during step d. of Hoffman to obtain the predicable result of separating compounds with different characteristics. One of ordinary skill would have been motivated to do so as taught by Shih to make the experimental platform smaller, perform automatic inspection instead of manual operation, reduce amounts of reagent, increase the manipulability, and reduce the time (para. [0004]). Regarding the reasonable expectation of success, Shih evidences methods of using centrifugal microfluidic biochips to separate compounds with different characteristics (step a4 Figures 14, b4 Figure 15, step c3 “Increasing the rotational speed by the driving module so that the first eluent overcomes the second valve to enter the transient pause chamber and the second eluent overcomes the third valve to enter the first decanting chamber” Figure 16; see Figures 14-16).
Regarding the preamble of claim 1, Hoffman teaches the method removes paraffin from the sample (see “extracting paraffin out of the paraffin-embedded tissue sample” abstract; see also claims; pg. 2 10-11th and 16th para.; pg. 3) and therefore the method steps taught by Hoffman are capable of meeting the intended use of “a method for deparaffinizing formalin-fixed paraffin-embedded tissue (FFPE)” as recited in the preamble. If the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). In the instant case, for the reasons stated above, Hoffman in view of Shih suggest all the active method steps of the instantly claimed structurally complete invention in the claim body and therefore meet instant claims.
Furthermore, regarding claim 1, it is noted that instant claims as written do not require a particular order. In Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003), the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order (see MPEP 2111.01 (II)).
Regarding claims 2-3, further to the discussion of claim 1 above, Hoffman teaches a step of introducing a fluid that contains an aqueous solution of lysis buffer (“the oil mixed with extracted paraffin is conveyed with an aqueous solution” pg. 2 para. 11-12).
Regarding claims 2-3, Applicant is directed to MPEP 2111.01 (II) which states that though understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. See also Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003). In the instant case, because the claimed steps do not specify an order, this step falls under the broadest reasonable interpretation of “introducing a fluid into the first chamber” performed after the paraffin removal with the aqueous solution buffer as “the fluid” and meets instant claims as written.
Regarding claim 6, further to the discussion of claim 1 above, Hoffman teaches step b. comprises introducing the fluid held in the biochip (“oil from a first reservoir” claims) into the first chamber ((“Introducing oil into the first chamber” claims pg. 1; pg. 2 3rd-4th, 9th and 13th para.).
Regarding claims 8-9, further to the discussion of claim 1 above, Hoffman teaches step c. comprises tempering the first chamber to a temperature that is greater than the melting point of paraffin (“due to the first temperature of the oil, the paraffin melts and combines with the oil”; pg. 3 19th para.) for a period of time. Although Hoffman is silent to specific temperature, Lim evidences paraffin wax melts at 50-60 degrees C (abstract), and therefore the temperature of the oil taught by Hoffman, which melts the paraffin, would be greater than 50-60 degrees C which is within the claimed range of > 49 °C (instant claim 8) and meets instant claims and overlaps with the claimed range of “55 °C to 65 °C” (instant claim 9).
Notably, regarding claims 8-9, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05. Therefore, in the instant case, the temperature that melts the paraffin of Hoffman, which as evidenced by Lim is 50-60 degrees C, makes the instantly claimed ranges of > 49 °C (instant claim 8) and “55 °C to 65 °C” (instant claim 9) and it would be routine procedure to optimize the temperature to melt the paraffin.
Regarding claim 10, further to the discussion of claim 8 above, Hoffman teaches step c. comprises tempering the first chamber for a second time to a temperature of between 70 °C and 90 °C (“between 70 °C and 90 °C ; abstract; see also pg. 2 12th para. and pg. 3 1st para.). Hoffman teaches the hearting to between 70 °C and 90 °C easily and effectively reverses fixation of formalin of the tissue (“fixation of formalin of the tissue by heating can be easily and effectively reversed” pg. 2 12th para.) and therefore this step is capable of meeting the claimed intended use of “for decrosslinking molecules contained in the tissue.”
Regarding claim 13, further to the discussion of claim 1 above, Hoffman teaches analyzing the liquid phase containing the tissue with respect to at least one molecular property (“DNA from cells of the tissue sample to be extracted” pg. 2 9th para. and “for a further analysis of the DNA” pg. 2 11th para.) and therefore it would be obvious to combine the additional step of analysis of the DNA of Hoffman.
Regarding the preamble of claim 13, the preamble merely states, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). In the instant case, for the reasons stated above, Hoffman in view of Shih suggest all the active method steps of the instantly claimed structurally complete invention in the claim body and therefore meet instant claims.
Hence, the claimed invention as a whole was prima facie obvious.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffman (WO-2017202729-A1; see IDS filed 15th, October, 2024; citations refer to attached translation) in view of Shih et al. (US-20210387179-A1; see IDS filed 15th, October, 2024; henceforth “Shih”) as applied to claim 1 above, and in further view of Qamar et al. (Saudi J Biol Sci. 2016 Sep 10;24(7):1465–1469.; henceforth “Qamar”).
The teachings of Hoffman and Shih above are incorporated herein in their entirety.
Regarding claims 4-5, further to the discussion of claim 1 above, although Hoffman teaches a step of introducing a fluid that contains an aqueous solution of lysis buffer (“the oil mixed with extracted paraffin is conveyed with an aqueous solution” pg. 2 para. 11-12) which falls under the broadest reasonable interpretation of step b. (see claims 2-3 rejection above), Hoffman and Shih are silent to including a proteinase (instant claim 4) of proteinase K (instant claim 5) in the lysis buffer.
Additionally, regarding claims 4-5, Qamar teaches Proteinase K in lysis buffer (Materials and methods “2.3.2. WBC lysis” pg. 1466). Qamar teaches Proteinase K is a broad spectrum protease, plays a central role and is responsible for digestion of all the proteins in the cell lysate and appropriate concentration of this enzyme is necessary in the lysate (pg. 1469 col. 1).
Therefore, regarding claims 4-5, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Hoffman in view of Shih, and combine the known prior art element of the Proteinase K of Qamar to obtain the predictable result of lysis buffer. One or ordinary skill would have been motivated to do so as taught by Qamar because it is a known component of lysis buffer protease, plays a central role and is responsible for digestion of all the proteins in the cell lysate (pg. 1469 col. 1). Regarding the reasonable expectation of success, Qamar evidences effective use of lysis buffer that includes Proteinase K (Materials and methods “2.3.2. WBC lysis” pg. 1466).
Hence, the claimed invention as a whole was prima facie obvious.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Hoffman (WO-2017202729-A1; see IDS filed 15th, October, 2024; citations refer to attached translation) in view of Shih et al. (US-20210387179-A1; see IDS filed 15th, October, 2024; henceforth “Shih”) as applied to claim 1 above, and in further view of Jung et al. (Lab Chip. 2012 May 7;12(9):1598-600. Epub 2012 Mar 22.; henceforth “Jung”).
The teachings of Hoffman and Shih above are incorporated herein in their entirety.
Regarding claim 7, further to the discussion of claim 1 above, although Hoffman teaches the tempering in step c. and in step e. is carried out by applying temperature with a heating device of the microfluidic system (claims; Figure 1 (130)), Hoffman and Shih are silent to applying temperature through a first chamber wall arranged transversely to the axis of rotation.
Nevertheless, regarding claim 7, Jung teaches a method that includes heating steps using a microfluidic biochip that uses a thermal block arranged transversely to the axis of rotation to subject the sample to temperatures (see Figure 1; pg. 1598 col. 1) that applies heat through chamber walls of the microchip. Jung teaches the thermal blocks allow for fast temperature control so that the process can be performed without need for the external pumping instrumentation and complicated fabrication process (pg. 1598 col. 2 1st para.).
Therefore, regarding claim 7, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Hoffman in view of Shih, and simply substitute the known prior art element of the thermal block arranged transversely to the axis of rotation to subject the sample to temperatures which applies heat through chamber walls of the microchip of Jung to obtain the predictable result of applying temperature with a heating device. One of ordinary skill would have been motivated to do so as taught by Jung to allow for fast temperature control without need for the external pumping instrumentation and complicated fabrication process (pg. 1598 col. 2 1st para.). Regarding the reasonable expectation of success, Jung evidences temperature control with thermal blocks arranges transversely to the axis of rotation to subject the sample to temperatures (see Figures 1-2; pg. 1598 col. 1).
Hence, the claimed invention as a whole was prima facie obvious.
Pertinent Art
The prior art of Wang et al. Wang et al. (CN-108424850-A; citations refer to attached translation) made of record but not relied upon is considered pertinent to Applicant’s disclosure.
Wang teaches a method for nucleic acid extraction from cells using a centrifugal microfluidic biochip (“a kind of micro-fluidic nucleic acid extraction chip of centrifugal force” abstract) comprising:
placing cells into a first chamber of a fluidic system (“A. Introduction of a blood sample” pg. 3)
introducing fluid into the first chamber (“First add protease to mix, then add lysate, then incubate at 56°C for 0 minutes” pg. 3)
Wang does not teach a formalin-fixed paraffin-embedded tissue (FFPE), a method step of deparaffinizing, or steps of melting, separating, or discharging paraffin.
Examiners Remark
Claims 11-12 are free of the prior art. However, these claims are not allowable because they are dependent on rejected claim 1, they are objected to above, and they are rejected under 35 U.S.C. 112 (b) above.
Conclusion
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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