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 Objections
Claim 5 is objected to because of the following informality:
a) claim 5 recites “. . . . the pH gradient results in improvements [plural] in characterization of the at least one analyte, and wherein the improvement [singular] in characterization . . . [emphasis by the Examiner] ” So, “improvements” should be -- improvement --.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Note that dependent claims will have the deficiencies of base and intervening claims.
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 1-20 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:
a) claim 1 requires
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These underlined features are confusing because on the one hand the at least one pH gradient compound is said to be part of the composition (“wherein the composition comprises at least one pH gradient compound, . . . .”), but on the other hand the claim seems to indicate that the pH gradient is formed by the at least one pH gradient compound that is not part of the composition (“create a pH gradient using the at least one pH gradient compound and separate the composition via isoelectric focusing . . . .).
b) claim 1 requires
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As the pH gradient is the basis for separating composition constituents in isoelectric focusing1 and claim 1 requires “wherein the composition comprises at least one pH gradient compound”, is claim 1 actually claiming that the at least one pH gradient compound, if not the pH gradient it forms, is separated?
c) claim 1 requires “and wherein the amine buffer is configured to modify the pH gradient.” This limitation is indefinite because there does not appear to be an initial pH gradient in the claim without the amine buffer, so it is not clear what modification could have occurred through the amine buffer.
d) claim 17 requires “. . . .: correlating the at least one analyte peak detected by imaging of the separation channel or a portion thereof with mass spectrometry data for the at least one separated analyte.” The scope of this limitation is not clear as it is not clear what such “imaging” would entail or appear as. An example from Applicant would be helpful in understanding this claim limitation.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 7-11, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suba et al., “Capillary isoelectric focusing method development and validation for investigation of recombinant therapeutic monoclonal antibody,” Journal of Pharmaceutical and Biomedical Analysis 114 (2015) 53–61 (hereafter “Suba”) as evidenced by the Millipore-Sigma product literature for Pharmalyte® 3-10 (hereafter “Millipore-Sigma”) and Wu et al., “Capillary lsoelectric Focusing Methods for Charge-based Analysis of Biotech Pharmaceutical Samples,” Chapter 26 in Bioseparation and Bioprocessing – A Handbook, volume 2, ed. Ganapathy Subramanian, 2nd edition, WILEY-VCH Verlag GmbH & Co. KGaA, 2007 (hereafter “Wu”).
Addressing claim 1, Suba discloses a method for analyzing at least one analyte (see the title), the method comprising:
introducing a composition (see 2.4. Sample solution, which is on page 54, and 3.5. Salt and urea content of the sample, which is on page 58) into a separation channel (see 2.2. Instrumentation, which is on page 54, noting especially “50µm inner-diameter fluorocarbon coated capillaries (µSil-FC)”, and see 2.5. General setup, which is on
page 54, noting especially “The injection was performed during 60 s with 20 psi hydrodinamical pressure, the . . . .” ) wherein the composition comprises at least one pH gradient compound (see again 2.4. Sample solution, noting especially, “The investigated sample solution contained 46% (v/v) HPMC solution, 41% (v/v) 0.5 mg/ml MAB solution, 3.2% (v/v) mixture of Pharmalyte 3–10 and 5–8 (1:5), ; . . . . [underlining by the Examiner]”. As evidenced by Millipore-Sigma, Pharmalyte comprises at least one pH gradient compound:
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Also see the first two parts of Wu 26.2.l Selection of Carrier Ampholytes on pages 739-743), an amine buffer (Tris – see again 3.5. Salt and urea content of the sample, noting especially, “50mM Tris solution was used to dilute the sample to 0.5 mg/ml, . . . .”), and at least one analyte of interest (“The investigated sample solution contained 46% (v/v) HPMC solution, 41% (v/v) 0.5 mg/ml MAB solution, . . . .”2);
applying an electric field across the separation channel to create a pH gradient (this step is implied by “Focusing voltage 20kV” and “Focusing voltage 25kV” in Table 1 and in Figure 2) using the at least one pH gradient compound and separate the composition via isoelectric focusing (see the electropherogram in Figures 1, 2, and 3), generating at least one focused analyte peak ( in the captions for Figures 1-3 note “1–5 are the sample peaks belonging to the different isoforms of the investigated monoclonal antibody MAB A.”).;
mobilizing the at least one focused analyte peak (in the Figure 1 caption note the following “. . . ., mobilization for 20 min at 30 kV with 100mM acetic acid.” This is also similarly stated in the captions for Figures 2 and 3.); and
wherein the amine buffer is configured to modify the pH gradient (Suba does not disclose that Tris is configured to modify the pH gradient. However, as acknowledged by Applicant it inherently does so. See Applicant’s originally filed specification paragraph [0053]. Note that Applicant’s specification is only being turned to show an inherent property of a compound. Moreover, Applicant claim 7 specifically mentions that the amine buffer may be Tris).
Addressing claim 7, for the additional limitation of this claim recall from the rejection of underlying clam 1 that the amine buffer in Suba is Tris.
Addressing claim 8, for the additional limitation of this claim note the following in Suba, “A capillary isoelectric focusing method was developed and validated for identification testing of monoclonal antibody drug products with isoelectric point between 7.0 and 9.0. [underlining by the Examiner]” See the Suba Abstract. This pI range is substantially the same as that claimed. (“between about 7.0 and about 9.5.”).
Addressing claim 9, for the additional limitation of this claim note the following in Millipore-Sigma
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Addressing claim 10, for the additional limitation of this claim note the following in Millipore-Sigma
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Addressing claim 11, for the additional limitation of this claim note the following in Suba,
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Addressing claim 15, the additional limitation of this claim may be inferred from the electropherograms in Figures 1-3 and the following
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Claims 2 and 3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suba as evidenced by Millipore-Sigma, Wu, and Lillard et al., “Analysis of single erythrocytes by injection-based capillary isoelectric focusing with laser-induced native fluorescence detection,” Journal of Chromatography B, 687 (1996) 363-369 (hereafter “Lillard”).
Addressing claim 2, as a first matter: (1) Suba as evidenced by Millipore-Sigma meets all of the limitations of claim 1 (see the rejection of claim 1 under
35 U.S.C. 102(a)(1) above), and (2) by the phrase “the pH gradient’s linearity…” the Examiner understands it in the conventional sense as exemplified by Lillard Figure 6 and 3.2. Linearity of the pH gradient, which is on page 368.3
As for the limitation “. . . ., wherein modification of the pH gradient comprises adjusting the pH gradient’s linearity…”, this is inherently met as the method and composition of Suba as evidenced by Millipore-Sigma is otherwise identical to that of claim 2. It has been held that something which is old does not become patentable upon the discovery of a new property. See MPEP 2112(I). Also, an inherent property need not be recognized at the relevant time. See MPEP 2112(II). Last, if the composition is physically the same, it must have the same properties. See MPEP 2112.01(II).
Addressing claim 3, as a first matter, there is not enough information in Suba to determine whether (the Tris-including composition at least) forms a linear or non-linear pH gradient. On the other hand, as noted in the rejection of underlying claim 2,
As for the limitation “. . . ., wherein modification of the pH gradient comprises adjusting the pH gradient’s linearity…”, this is inherently met as the method and composition of Suba as evidenced by Millipore-Sigma is otherwise identical to that of claim 2. It has been held that something which is old does not become patentable upon the discovery of a new property. See MPEP 2112(I). Also, an inherent property need not be recognized at the relevant time. See MPEP 2112(II). Last, if the composition is physically the same, it must have the same properties. See MPEP 2112.01(II).
For the same reasons as expressed above, the additional limitation of claim 3 is considered inherent to the method of Suba as modified by Millipore-Sigma.
Claim 4 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suba as evidenced by Millipore-Sigma and Wu, and David Hausfeld US 4,401,538 (hereafter “Hausfeld”).
Addressing claim 4, as a first matter: (1) Suba as evidenced by Millipore-Sigma meets all of the limitations of claim 1 (see the rejection of claim 1 under
35 U.S.C. 102(a)(1) above), and (2) by the phrase “a shallow pH gradient…” the Examiner understands it in the conventional sense as exemplified by Hausfeld col. 2:25-29.4
As for the limitation “. . . ., wherein the modification of the pH gradient results in a shallow pH gradient…”, this is inherently met as the method and composition of Suba as evidenced by Millipore-Sigma is otherwise identical to that of claim 4. It has been held that something which is old does not become patentable upon the discovery of a new property. See MPEP 2112(I). Also, an inherent property need not be recognized at the relevant time. See MPEP 2112(II). Last, if the composition is physically the same, it must have the same properties. See MPEP 2112.01(II).
Claim 6 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suba as evidenced by Millipore-Sigma, Wu, and the NIH National Library of Medicine – PubChem information sheet about the compound Tris(hydroxymethyl)aminomethane (hereafter “PubChem”).
Addressing claim 6, as a first matter, Suba as evidenced by Millipore-Sigma meets all of the limitations of claim 1 (see the rejection of claim 1 under
35 U.S.C. 102(a)(1) above).
As for the claim limitation “. . . ., wherein the amine buffer has a pKa of about 6.0 to about 8.5…”, recall from the rejection of underlying clam 1 that the amine buffer in Suba is Tris. As evidence by PubChem the pka of Tris equals 8.07, which is within the claimed range:
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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 16, 18, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Suba as evidenced by Millipore-Sigma and Wu, and in view of Zhang et al., Mass spectrometry for the biophysical characterization of therapeutic monoclonal antibodies,“ FEBS Letters 588 (2014) 308-317 (hereafter “Zhang”), and McGivney et al. US 2015/0162177 A1 (hereafter “McGivney”).
Addressing claim 16, as a first matter, Suba as evidenced by Millipore-Sigma meets all of the limitations of claim 15 (see the rejection of claim 15 under 35 U.S.C. 102(a)(1) above).
Suba as evidenced by Millipore-Sigma does not disclose “. . . ., expelling the at least one mobilized analyte peak into a mass spectrometer and generating mass spectrometry data.” As best understood by the Examiner the analyte(s) in Suba are detected by UV/Vis spectrometry. See the absorbance spectra in Figures 1-3 and note the following in 2.1. Materials, “. . . .and UV–visible synthetic cIEF markers . . . .”
McGivney discloses “a method and system for on-line coupling of capillary isoelectric focusing (cIEF) to high-resolution mass spectrometry . . . .” See the Abstract. McGivney allows for the cIEF method to be similar to that disclosed by Suba. See p[paragraphs [0035], [0041], [0043], [00442], [0050], [0051], and [0122].
Zhang outlines various mass spectrometry-based strategies for biophysical characterization of monoclonal antibodies, which are the analytes in Suba. See in Zhang the title and Abstract.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to adapt the method of Suba as evidenced by Millipore-Sigma to be able to expel the at least one mobilized analyte peak into a mass spectrometer and generate mass spectrometry data .because
(1) this will provide complementary information to the UV/VIS spectra of Suba. While the UV/Vis spectra allow for the monoclonal antibodies in the sample to identified and quantified, the mass spectra will allow biophysical information, such as structural information, about the antibodies to be obtained. See Zhang the Abstract and 2.2.3. Top-down fragmentation, which is on page 310, and Figure 2; and
(2) as shown by McGivney one of ordinary skill in the art would know how implement such mass spectrometry adaptation to the method of Suba as evidenced by Millipore-Sigma.
Addressing claim 18, for the additional limitation of this claim note the following in Suba, “A method was developed providing good pH gradient for internal calibration (R2 > 0.99) . . . .[italicizing by the Examiner]”
Addressing claim 19, one of ordinary skill in the art would recognize that a linear calibration curve is implied by Suba as “R2” is conventionally understood to represent the coefficient of regression of a linear regression.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Suba as evidenced by Millipore and Wu, and in view of Zhang and McGivney as applied to claims 16, 18, and 19 above, and further in view of Elnagar et al. US 2025/0003922 A1 (hereafter “Elnaggar”).
Addressing claim 17, as a first matter, it is not clear what is meant by “correlating the at least one analyte peak detected by imaging of the separation channel or a portion thereof with mass spectrometry data for the at least one separated analyte.” As best understood by the Examiner such “correlating’ may be as shown in Figures 25-29, 31A, and 31B of Elnaggar. See also Elnaggar the title, Abstract, and paragraphs[ 0056]-[0059], [0063], [0088], [0094], [0115]-[0119], [0132]- [0138], [0170], and [0212].
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to adapt the method of Suba as evidenced by Millipore and as modified by Zhang and McGivney to correlate the at least one analyte peak detected by imaging of the separation channel or a portion thereof with mass spectrometry data for the at least one separated analyte as taught by Elnaggar because Elnaggar discloses
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15. Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Suba as evidenced by Millipore and Wu, and in view of Zhang and McGivney as applied to claims 16, 18, and 19 above, and further in view of Cao et al., “Charge profiling and stability testing of biosimilar by capillary isoelectric focusing,” Electrophoresis 2014, 35, 1461–1468 (hereafter “Cao”).
Addressing claim 20, although Suba as evidenced by Millipore and as modified by Zhang and McGivney dos not explicitly disclose “. . . ., wherein the calibration curve is used to determine the pI value of an unknown analyte…”, It would have been obvious to one of ordinary skill in the art at the time of the effective filing date of the application to do so because it is arguably implied by “A method was developed providing good pH gradient for internal calibration (R2 > 0.99) . . . .[italicizing by the Examiner]” in the Suba Abstract. Additionally, it is strongly suggested by the following, which is also in Suba, “Capillary isoelectric focusing (cIEF) is a powerful tool to characterize charge profile of the monoclonal antibodies, because different charge variants can be distinguished according to their isoelectric points using internal calibration [9].” See Suba the last full sentence on page 53. Endnote [9] is Cao, which discloses5,
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See Cao 3.3.2Precision, which is on page 1466.
Allowable Subject Matter
Claims 5 and 12-14 would be allowable if rewritten to overcome the rejections under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
a) in claim 5 the combination of limitations requires the following underlined features
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However, for Suba as evidenced by Millipore-Sigma based on Suba Figures 3(a) and 3(c) reproduced below, the separation of the at least one analyte slightly deteriorated (especially for peak 3) compared to that attained in a method which does not comprise the amine buffer:
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b) in claim 12 the combination of limitations requires the following underlined feature
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In contrast, Suba discloses
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c) in claim 13 the combination of limitations requires the following underlined features
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In contrast, Suba discloses
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d) in claim 14 the combination of limitations requires the following underlined feature
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In contrast, while Suba as evidence by Millipore-Sigma does disclose “. . . ., wherein the at least one focused analyte peak is mobilized using . . . . a chemical mobilizer, . . .”, Suba dopes not disclose “. . . , wherein the anodic stabilizer is used as a chemical mobilizer…”:
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER STEPHAN NOGUEROLA whose telephone number is (571)272-1343. The examiner can normally be reached on Monday - Friday 9:00AM-5:30 PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Luan Van can be reached on 571 272-8521. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER S NOGUEROLA/ Primary Examiner, Art Unit 1795
1 Se Applicant’s originally filed specification paragraph [0002].
2 MAB stands for monoclonal antibodies. See the first sentence of 1. Introduction.
3 If Applicant intends for this phrase to be understood in an unconventional sense, please heed MPEP 2173.05(a).
4 If Applicant intends for this phrase to be understood in an unconventional sense, please heed MPEP 2173.05(a).
5 MT stands for migration time. See Cao 3.1.1 Urea, first sentence, which is on page 1463.