Prosecution history

As seen in the diagram, the ‘179 patent is a member of a family of patents and patent applications. The initial application was filed in August 1989. For help in interpreting the meaning and scope of the claims, prosecution histories are consulted from each of applications and patents in the boxes below.

US Application No: 07/398,217

The submitted claims were all directed to the invention as applied to the MHC locus. No substantive prosecution happened in this case. The application was abandoned in favour of the continuation-in-part.

US Application No: 07/405,499

The submitted claims were directed to the invention as applied to the MHC locus. No substantive prosecution happened in this case. The application was abandoned in favour of the continuation application

US Application No: 07/465,863

The submitted claims were again directed to RFLP analysis of amplifying non-coding sequence of the MHC locus to identify MHC alleles. In a first examination, the Examiner believed that the claims encompassed two inventions 12. The claims directed to methods and kits for MHC typing were chosen for prosecution and were rejected 13 as being obvious over a method for PCR-RFLP analysis of a c-ras gene (Deng and Mullis, Nucl Acid Res 16: 6231, 1988) in combination with either of two articles about a method for RFLP analysis of the MHC class II region.

The gist of the argument against this rejection is that (i) intron sequences are not random but “reflective of adjacent and remote allele sequences on the same chromosome”; (ii) amplifying intron DNA enables complete distinction between all alleles of a MHC gene locus; and (iii) the invention distinguishes heterozygotes and homozygotes. 14 The applicant then explains how prior to this invention, it was not believed that PCR and RFLP could be combined to distinguish MHC alleles. A lengthy exposition follows in which the applicant distinguishes his invention particularly from the cited prior art. The Examiner does not buy this argument however. Citing additional references demonstrating RFLP sites in intron sequences, the Examiner concludes basically that the Applicant is wrong.

In another response, the Applicant contends that “[u]ntil one recognizes that the intron sequences provide more variations and the variations correlate with the alleles, one cannot select a sufficiently informative sequence that is small enough to amplify.” 15 This is the essence of the response to all subsequent art rejections.

After the Examiner repeats the rejection, the application is abandoned.

US Application No: 07/551,239 (Patent No. 5,192,659)

Claims submitted in this continuation-in-part are directed to the more general case of using the invention to detect alleles of a genetic locus 16.

Claim 1 recited: A method for detection of at least one allele of a genetic locus comprising amplifying genomic DNA with an intron-spanning primer pair that defines a DNA sequence, said DNA sequence being in genetic linkage with said genetic locus and containing a sufficient number of intron sequence nucleotides to produce an amplified DNA sequence characteristic of said allele.[add a comment]

Without going into detail, the rejections for obviousness and the responses by the Applicant iterate those in the prior application. In response to citations of the prior art in which a “sequence polymorphism in an intron was empirically determined to correlate with a particular allele of a genetic locus, e.g. … β-thalassemia” 17, the Applicant amended the claim to the analysis of multi-allelic genetic loci. With respect to articles that describe RFLP sites in introns, the Applicant responded that because about 95% of DNA is non-coding, about 95% of restriction sites should be located there. But that fact did “not teach that intron sequences can be amplified and analysed to identify the alleles.” 18 The Applicant stresses that it takes an exhaustive search to find an RFLP that correlates with a particular allele, in contrast to the invention in which one only needs to know how the degree of polymorphism in order to amplify a sufficiently large piece of non-coding DNA to allow identification of all the alleles.

In the next Office Action, the Examiner additionally rejects the claims for lack of enablement, that is, the application does not teach how to use the invention for any region of DNA other than the MHC region. Despite protestations by the Applicant that the rejection should have been raised earlier and that the rejection lacks particularity, the Examiner refused to let up on either rejection. In response to the enablement rejection, the Applicant submits several declarations by prominent scientists who state that the generality of the invention was unexpected.

After several more rounds of rejections and responses, the claims were finally limited to the invention as it applied to MHC genes. The Examiner allowed these claims

US Application No: 07/949,652 (Patent No. 5,612,179)

The claims submitted in this application contains claims directed to the invention applied generally and claims directed to the invention applied to MHC genes. Claim 1 as submitted is the same as claim 1 of the patent except it lacks the analyzing step; claim 7 as submitted is the same as claim 9 of the patent.

Of interest, in a Preliminary Amendment 19 (an amendment submitted before the first Office Action), the invention is further characterized as not requiring information regarding family members. Furthermore, several methods specifically excluded from the claims are enumerated. These include “identifying a marker which could be used as a site of polymorphism to determine inheritance in family studies”; “sites of polymorphism in non-coding regions to attempt to track inheritance of disease genes in family studies”; classical RFLP analyses; and use of VNTR sequences as markers, such as for paternity testing and forensic applications.

A new Examiner in this case also rejected claims for lack of enablement and only rejected claims drawn to methods to determine RFLP fragments of an MHC locus for obviousness, although citing different prior art. While overcoming the lack of enablement rejection with the submission of declarations by prominent scientists, the Applicant was unable to overcome the prior art rejection for obviousness. By canceling the rejected claims, the remaining claims should have been allowed.

The case was transferred to a new examiner however, who re-opened the prosecution and rejected the claims for lack of enablement. This remained a very difficult rejection to overcome as the Examiner criticized the statements in the Declarations and would not accept them as persuasive. Furthermore, the Examiner rejected claims as obvious over Kan et al. (identified RFLP near the β-globin gene) with a PCR reference. An interview with the Examiner and senior supervisor was used to discuss and resolve the issues of the Declarations and prior art. Following presentation of the interview as an amendment, the claims were allowed.